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University of Rochester
1.
Folts, Christopher.
Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division.
Degree: PhD, 2014, University of Rochester
URL: http://hdl.handle.net/1802/28963
► A great many molecular and metabolic components of processes of self-renewal and cell cycle exit have been described in detail for the oligodendrocyte progenitor (O-…
(more)
▼ A great many molecular and metabolic components
of processes of self-renewal
and cell cycle exit have been
described in detail for the oligodendrocyte progenitor (O-
2A/OPC)
cell—a cell needed to generate myelinating oligodendrocytes during
the
development of and repair of the central nervous system—but
these have not been
organized into a cohesive network with
considerable predictive value. Here, we present
data indicating
that activation by toxicological and physiological pro-oxidants of
a
signaling pathway we recently identified and characterized,
termed the Redox/Fyn/c-Cbl
(RFC) pathway, suppresses a network of
mitogenic signaling molecules, including cell
cycle regulatory
proteins, needed to undergo self-renewing divisions in a
c-Cbldependent
manner. Unexpectedly, we find with an in vitro
model of the demyelinating
lysosomal storage disorder Krabbe
Disease that RFC-dependent regulation of cell
division is
secondary to endolysosomal homeostasis. In this context we
identify
physicochemically diverse protective agents that reduce
toxicities and restore critical O-
2A/OPC progenitor cell
functions, including self-renewal, by positive modulation of
lysosomal pH. Moreover, we find that toxic lipids accumulating in
other lysosomal
storage disorders perturb progenitor cell
behaviors by elevation of lysosomal pH,
suggesting a general
principle of lyso-lipid toxicity.
Subjects/Keywords: Oligodendrocyte Progenitor Cell; Lysosomal Storage Disease; Redox
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APA (6th Edition):
Folts, C. (2014). Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/28963
Chicago Manual of Style (16th Edition):
Folts, Christopher. “Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division.” 2014. Doctoral Dissertation, University of Rochester. Accessed January 16, 2021.
http://hdl.handle.net/1802/28963.
MLA Handbook (7th Edition):
Folts, Christopher. “Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division.” 2014. Web. 16 Jan 2021.
Vancouver:
Folts C. Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division. [Internet] [Doctoral dissertation]. University of Rochester; 2014. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1802/28963.
Council of Science Editors:
Folts C. Redox/Fyn/c-Cbl–Dependent and –Independent Regulation of
Oligodendrocyte Progenitor Cell Division. [Doctoral Dissertation]. University of Rochester; 2014. Available from: http://hdl.handle.net/1802/28963

Erasmus University Rotterdam
2.
B.J. Ebbink (Johanneke).
Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte.
Degree: 2017, Erasmus University Rotterdam
URL: http://hdl.handle.net/1765/102773
► markdownabstractIn this thesis we focus on the brain and the neuropsychological sequelae in patients with lysosomal storage disorders (LSDs). Up till now studies on the…
(more)
▼ markdownabstractIn this thesis we focus on the brain and the neuropsychological sequelae in patients with lysosomal storage disorders (LSDs). Up till now studies on the consequences of brain involvement for neuropsychological development in patients with LSDs is limited. Although most LSDs have in common that they are caused by a single lysosomal enzyme deficiency, the storage products differ and as a consequence the effect on the brain and cognitive development varies between the different
Subjects/Keywords: enzyme replacement therapy; lysosomal storage disease; enzyme deficiency; lysosomal storage disorders (LSDs)
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APA (6th Edition):
(Johanneke), B. E. (2017). Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte. (Thesis). Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/102773
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
(Johanneke), B.J. Ebbink. “Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte.” 2017. Thesis, Erasmus University Rotterdam. Accessed January 16, 2021.
http://hdl.handle.net/1765/102773.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
(Johanneke), B.J. Ebbink. “Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte.” 2017. Web. 16 Jan 2021.
Vancouver:
(Johanneke) BE. Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte. [Internet] [Thesis]. Erasmus University Rotterdam; 2017. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1765/102773.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
(Johanneke) BE. Long-term Neuropsychologic Outcome in Children Diagnosed with a Lysosomal Storage Disease: Lange termijn neuropsychologische gevolgen bij kinderen gediagnosticeerd met een lysosomale stapelingsziekte. [Thesis]. Erasmus University Rotterdam; 2017. Available from: http://hdl.handle.net/1765/102773
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Adelaide
3.
McIntyre, Chantelle.
Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA.
Degree: 2014, University of Adelaide
URL: http://hdl.handle.net/2440/101514
► Gene therapy is promising for the treatment of monogenetic disorders because it aims to restore overall homeostasis, not by treating disease symptoms, but by targeting…
(more)
▼ Gene therapy is promising for the treatment of monogenetic disorders because it aims to restore overall homeostasis, not by treating
disease symptoms, but by targeting the fundamental cause of
disease. Viral vectors are valuable tools for mediating the transfer of therapeutic genes to target cells, and lentiviral vectors in particular are well suited to this role as they chromosomally integrate, can enter dividing and non-dividing cells, and evoke little or no immune response. The aim of the current thesis was to evaluate the potential of using lentiviral-mediated gene therapy for the treatment of mucopolysaccharidosis type IIIA (MPS IIIA), a heritable
lysosomal storage disorder affecting the central nervous system (CNS). The chronic and progressive course of MPS IIIA results from
lysosomal accumulation of heparan sulphate (a highly sulphated glycosaminoglycan), secondary to deficiency of the
lysosomal hydrolase sulphamidase. Accumulation of heparan sulphate within the cells of the reticulo-endothelial system, the monocyte-macrophage system, and neurons, leads to hepatosplenomegaly and severe, progressive neuropathology in affected children, and ultimately to death at around 15 years of age. There are currently no effective treatments for MPS IIIA patients. The somatic and CNS aspects of pathology in a mouse model of MPS IIIA were addressed in this study using two separate methods of therapeutic gene delivery; intravenous gene delivery, which directs gene transfer to the liver, and gene delivery to the brain via the cerebral lateral ventricles which utilises the cerebrospinal fluid to achieve gene distribution throughout the brain. After intravenous administration of a self-inactivating lentiviral vector expressing murine sulphamidase to young adult MPS IIIA mice, the livers of treated animals were effectively modified to express high levels of therapeutic sulphamidase. The resultant widespread delivery of enzyme secreted from transduced cells to somatic tissues via the peripheral circulation corrected most somatic pathology, furthermore, markers of MPS IIIA pathology within the brains of treated mice were significantly reduced. When liver directed gene therapy was repeated in a second cohort of mice, however, similar benefits to the brain were not observed, presumably because the resulting levels of peripherally circulating enzyme were comparatively low. Although, in common with the first study, somatic pathologies still were corrected. Alternatively, lentivirus delivered to the brains of MPS IIIA mice via the cerebral lateral ventricles achieved extensive sulphamidase gene distribution and reduced
lysosomal storage throughout the brain. Improvements in behaviour were observed for these animals, as was the complete prevention of pathological urine retention. The blood-brain-barrier (BBB) limits the transfer of therapeutic enzymes from the blood to the brain, therefore gene therapy approaches to treat CNS pathology in the MPS are to either challenge the BBB with high levels of circulating enzyme, or bypass it…
Advisors/Committee Members: Anson, Donald Stewart (advisor), Byers, Sharon (advisor), School of Paediatrics and Reproductive Health (school).
Subjects/Keywords: gene therapy; lysosomal storage disease; neurodegenerative disorder; viral vector; mouse model
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
McIntyre, C. (2014). Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/101514
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
McIntyre, Chantelle. “Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA.” 2014. Thesis, University of Adelaide. Accessed January 16, 2021.
http://hdl.handle.net/2440/101514.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
McIntyre, Chantelle. “Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA.” 2014. Web. 16 Jan 2021.
Vancouver:
McIntyre C. Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA. [Internet] [Thesis]. University of Adelaide; 2014. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/2440/101514.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
McIntyre C. Lentiviral-mediated gene therapy for mucopolysaccharidosis type IIIA. [Thesis]. University of Adelaide; 2014. Available from: http://hdl.handle.net/2440/101514
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Iowa State University
4.
Jamil, Maryam.
Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model.
Degree: 2016, Iowa State University
URL: https://lib.dr.iastate.edu/etd/15726
► The Mucopolysaccharidoses (MPS) are a class of lysosomal storage disorders, characterized by the primary lysosomal storage of either single or multiple species of glycosaminoglycan (GAG)…
(more)
▼ The Mucopolysaccharidoses (MPS) are a class of lysosomal storage disorders, characterized by the primary lysosomal storage of either single or multiple species of glycosaminoglycan (GAG) which leads to cell, tissue, and organ dysfunction. This is manifested clinically by either bone/connective tissue disease, central nervous system (CNS) disease, or both, and often results in premature death. Mucopolysaccharidosis type III is a heterogeneous neuropathological disorder characterized by an accumulation of the heparan sulfate (HS). Of the four known types of MPS III in humans (A (OMIM: 252900), B (252920), C (252930), D (252940)), all have murine models except IIID. Additional to primary HS storage there is secondary lysosomal accumulation of multiple biological products including gangliosides. Mouse models are critical for advancing therapies for patients. Herein we describe the first mouse model of IIID.
The MPS IIID knockout lacks exons 2-13 of the 14 exons of N-Acetylglucosamine 6-Sulfatase (GNS) gene which encodes the enzyme (N-Acetylglucosamine 6-Sulfatase, EC 3.1.6.14) taking part in HS degradation pathway. Affected MPS IIID mice were compared to affected MPS IIIB and IIIA mice, as well as to wild type (WT) mice. Affected IIID animals had urine retention, hepatomegaly, and rough hair coat beginning at nine months, a phenotype similar to other forms of MPS III. Affected animals were further characterized by histology and biochemistry (at four, eight and twelve months), and behavior. At four months of age there was no detectable liver activity of GNS and an exponential increase of GAGs was seen. Mild vacuolation, particularly in CNS, was seen in hematoxylin and eosin (H&E) stained tissues of IIID affected mice. At twelve months H&E staining showed extensive vacuolation in hepatocytes, renal tubular cells, CNS, as well as cerebellar Purkinje cell loss. Luxol Fast Blue (LFB) staining of CNS tissue showed positive staining for glycosphingolipids. The preliminary behavioral assessment data showed that IIID mice perform better on rotorod at least until 12 months of age compared to IIIB mice.
Our findings of IIID mouse are consistent with the histological and biochemical findings in humans. Furthermore, it has a similar phenotype and pathology to other MPS III murine models.
Subjects/Keywords: Lysosomal storage disease; Metabolic disorder; Mucopolysaccharidosis; Neurodegeneration; Genetics
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Jamil, M. (2016). Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model. (Thesis). Iowa State University. Retrieved from https://lib.dr.iastate.edu/etd/15726
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jamil, Maryam. “Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model.” 2016. Thesis, Iowa State University. Accessed January 16, 2021.
https://lib.dr.iastate.edu/etd/15726.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jamil, Maryam. “Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model.” 2016. Web. 16 Jan 2021.
Vancouver:
Jamil M. Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model. [Internet] [Thesis]. Iowa State University; 2016. [cited 2021 Jan 16].
Available from: https://lib.dr.iastate.edu/etd/15726.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jamil M. Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model. [Thesis]. Iowa State University; 2016. Available from: https://lib.dr.iastate.edu/etd/15726
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Adelaide
5.
Whyte, Lauren Sue.
The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia.
Degree: 2019, University of Adelaide
URL: http://hdl.handle.net/2440/123399
► Alzheimer’s disease, the most common form of dementia, is characterised by extracellular amyloid beta plaques and intraneuronal tau tangles. While it is not fully understood…
(more)
▼ Alzheimer’s
disease, the most common form of dementia, is characterised by extracellular amyloid beta plaques and intraneuronal tau tangles. While it is not fully understood why these pathological hallmarks develop, several biological systems are believed to be involved. Of these,
lysosomal network dysfunction is an increasingly recognised pathogenic factor.
Lysosomal network disruptions, including upregulated endocytosis, aberrant trafficking and
storage of undegraded substrates, commence from the earliest stages of Alzheimer’s
disease. The importance of the
lysosomal network for neuronal health is underscored by the existence of more than 50
lysosomal storage disorders, which arise from the deficiency of an enzyme or other protein required for
lysosomal function. Many
lysosomal storage disorders have a severe neurodegenerative phenotype, most are recessively inherited, and until recently, heterozygotes were considered asymptomatic carriers. However, there is increasing evidence of some pathophysiology in heterozygotes, especially during ageing. This study aimed to investigate the impact of a heterozygous
lysosomal storage disorder allele (Hexb+/-) in an Alzheimer’s mouse model (AppNL-G-F/NL-G-F). We hypothesised Hexb heterozygosity would hasten and/or exacerbate pathology and
disease-related signs in AppNL-G-F/NL-G-F mice. The AppNL-G-F/NL-GF knock-in mouse was novel and not extensively characterised at the beginning of this PhD study. We therefore performed a behavioural test battery, and examined the
lysosomal network, in six-monthold AppNL-G-F/NL-G-F mice. AppNL-G-F/NL-G-F mice did not have memory impairments detectable in a Y-maze, novel object recognition test or Morris water maze at six-months. They did, however, exhibit reduced open field activity and
lysosomal network disruptions. Lysosome-associated membrane protein 1 and cathepsins B, L and D accumulated at amyloid beta plaques in AppNL-G-F/NL-G-F mice, presenting at the earliest and smallest plaques observed. AppNL-G-F/NL-G-F mice also exhibited elevated activity of β- hexosaminidase and cathepsins D/E and elevated levels of cathepsin D and LC3-II in the cerebral cortex, as determined by Western blot. AppNL-G-F/NL-G-F mice were intercrossed with Hexb+/- mice to determine the effect of heterozygosity of Hexb in the Alzheimer’s mouse. No substantial memory impairments or increases in key neuropathological markers of Alzheimer’s
disease were found. However, AppNL-G-F/NL-G-F; Hexb+/- mice demonstrated subtle impairments in behavioural flexibility during the reversal phase of the Morris water maze. AppNL-G-F/NL-G-F; Hexb+/+ mice had reduced activity in an open field and on the Y-maze. This phenotype was not exacerbated in AppNL-G-F/NL-G-F; Hexb+/- mice, but was reproduced by Hexb heterozygosity alone, in Appwt/wt; Hexb+/- mice. Heterozygosity of Hexb in AppNL-G-F/NL-G-F mice did not increase glial fibrillary acidic protein or ionised calcium binding adaptor molecule 1, markers of astrocytes and microglia, respectively. Nor did it lead to increased GM2…
Advisors/Committee Members: Hopwood, John (advisor), Sargeant, Tim (advisor), Hemsley, Kim (advisor), Lau, Adeline (advisor), Adelaide Medical School (school).
Subjects/Keywords: Alzheimer's Disease; dementia; lysosome; lysosomal storage disorder; beta-hexosaminidase
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Whyte, L. S. (2019). The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/123399
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Whyte, Lauren Sue. “The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia.” 2019. Thesis, University of Adelaide. Accessed January 16, 2021.
http://hdl.handle.net/2440/123399.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Whyte, Lauren Sue. “The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia.” 2019. Web. 16 Jan 2021.
Vancouver:
Whyte LS. The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia. [Internet] [Thesis]. University of Adelaide; 2019. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/2440/123399.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Whyte LS. The role of heterozygous lysosomal storage disorder alleles as risk factors for dementia. [Thesis]. University of Adelaide; 2019. Available from: http://hdl.handle.net/2440/123399
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
6.
Hermans, Monique.
Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II.
Degree: 1993, Erasmus University Medical Center
URL: http://hdl.handle.net/1765/13746
Subjects/Keywords: lysosomal a-glucosidase; storage disease
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hermans, M. (1993). Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/13746
Chicago Manual of Style (16th Edition):
Hermans, Monique. “Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II.” 1993. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 16, 2021.
http://hdl.handle.net/1765/13746.
MLA Handbook (7th Edition):
Hermans, Monique. “Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II.” 1993. Web. 16 Jan 2021.
Vancouver:
Hermans M. Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 1993. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1765/13746.
Council of Science Editors:
Hermans M. Structural and Functional Analysis of Lysosomal a-Glucosidase in Relation to Glycogen Storage Disease Type II. [Doctoral Dissertation]. Erasmus University Medical Center; 1993. Available from: http://hdl.handle.net/1765/13746

University of Sydney
7.
Fletcher, Jessica Louise.
Pathophysiology of canine fucosidosis
.
Degree: 2013, University of Sydney
URL: http://hdl.handle.net/2123/10420
► Pathophysiology of Canine Fucosidosis by Jessica L Fletcher Understanding processes involved in the onset and progression of fucosidosis, a childhood neurodegenerative lysosomal storage disease, is…
(more)
▼ Pathophysiology of Canine Fucosidosis by Jessica L Fletcher Understanding processes involved in the onset and progression of fucosidosis, a childhood neurodegenerative lysosomal storage disease, is critical to the development of effective treatment. Fucosidosis is caused by deficiency of the lysosomal hydrolase α-L-fucosidase due to inherited mutations in the FUCA1 gene. Canine fucosidosis, the only preserved animal model, was used to characterise preclinical pathophysiology, to establish potential markers of disease progression and test their capacity to measure responses to early therapy. Statistical interrogation of clinical data revealed that clinical signs are consistent from 12 months, and that rapid decline is signalled by sensory dysfunction from 18 months of age. Regression analysis against existing neuropathological data identified apoptosis and neuroinflammation as significant contributors to clinical dysfunction. Gene expression profiling of the frontal cortex at 16 weeks identified neuroinflammation to be prominent in fucosidosis pathogenesis (33% of differentially expressed genes) with both neuroinflammatory and mitochondrial-mediated pathways contributing to apoptotic cell death. Myelin genes were significantly downregulated, prompting investigation of oligodendrocyte populations in preclinical disease. Mature oligodendrocytes were reduced by 45-67%. Intracisternal enzyme replacement therapy from 8-16 weeks improved oligodendrocyte survival by 21%, and 29% of Purkinje neurons demonstrated reduced vulnerability to apoptosis. Neuroinflammatory cytokines and chemokines were investigated in cerebrospinal fluid to identify candidate biomarkers. MCP-1/CCL2 and KC/CXCL1 demonstrated potential, with significant increases with disease progression, and reductions with enzyme replacement therapy. Overall, these findings provide tools for disease management and a revised model of pathophysiology which can be used as a framework for future investigations into fucosidosis pathogenesis and therapy.
Subjects/Keywords: Lysosomal storage disease;
Canine animal model;
Fucosidosis;
Enzyme replacement therapy
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Fletcher, J. L. (2013). Pathophysiology of canine fucosidosis
. (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/10420
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Fletcher, Jessica Louise. “Pathophysiology of canine fucosidosis
.” 2013. Thesis, University of Sydney. Accessed January 16, 2021.
http://hdl.handle.net/2123/10420.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Fletcher, Jessica Louise. “Pathophysiology of canine fucosidosis
.” 2013. Web. 16 Jan 2021.
Vancouver:
Fletcher JL. Pathophysiology of canine fucosidosis
. [Internet] [Thesis]. University of Sydney; 2013. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/2123/10420.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Fletcher JL. Pathophysiology of canine fucosidosis
. [Thesis]. University of Sydney; 2013. Available from: http://hdl.handle.net/2123/10420
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Victoria University of Wellington
8.
Hammond, Natalie.
Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model.
Degree: 2016, Victoria University of Wellington
URL: http://hdl.handle.net/10063/9089
► Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late…
(more)
▼ Niemann-Pick type C (NPC)
disease is a rare neuro-visceral,
lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/
lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC
disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC
disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC
disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver
disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver
disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC
disease.
Advisors/Committee Members: Munkacsi, Andrew.
Subjects/Keywords: Lysosomal storage disease; Niemann-Pick type C Disease; Histone deacetylase inhibitor therapy; Lipid accumulation
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APA ·
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Manager
APA (6th Edition):
Hammond, N. (2016). Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/9089
Chicago Manual of Style (16th Edition):
Hammond, Natalie. “Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model.” 2016. Masters Thesis, Victoria University of Wellington. Accessed January 16, 2021.
http://hdl.handle.net/10063/9089.
MLA Handbook (7th Edition):
Hammond, Natalie. “Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model.” 2016. Web. 16 Jan 2021.
Vancouver:
Hammond N. Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model. [Internet] [Masters thesis]. Victoria University of Wellington; 2016. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10063/9089.
Council of Science Editors:
Hammond N. Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model. [Masters Thesis]. Victoria University of Wellington; 2016. Available from: http://hdl.handle.net/10063/9089

University of Toronto
9.
Lopez Vasquez, Lucia.
Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line.
Degree: 2017, University of Toronto
URL: http://hdl.handle.net/1807/79382
► Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A (α-gal A). Enzyme replacement therapy (ERT) consists of regular infusions…
(more)
▼ Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A (α-gal A). Enzyme replacement therapy (ERT) consists of regular infusions of recombinant α-gal A. Fabry disease patients commonly develop IgG antibodies against this enzyme and there is a concern that they may reduce the efficacy and safety of ERT. We developed an ELISA to measure anti-α-gal A IgG antibodies and found that 61% of patients on ERT were seropositive. We also designed a fast, single-chromatography purification protocol for α-gal A from the supernatant of a human embryonic kidney 293T cell line engineered to stably overexpress a 6xhis-tagged human α-gal A. We obtained 0.342 mg/L with the expected molecular weight but lower enzymatic activity than expected. This α-gal A is bound by antibodies from seropositive patients and not by those from healthy individuals, which suggests that it may serve as antigen in our ELISA to measure anti-α-gal A antibodies.
M.Sc.
Advisors/Committee Members: Medin, Jeffrey A, Medical Science.
Subjects/Keywords: alpha-galactosidase A; antibodies; ELISA; Fabry disease; lysosomal storage disorder; protein purification; 0566
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APA ·
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MLA ·
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APA (6th Edition):
Lopez Vasquez, L. (2017). Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/79382
Chicago Manual of Style (16th Edition):
Lopez Vasquez, Lucia. “Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line.” 2017. Masters Thesis, University of Toronto. Accessed January 16, 2021.
http://hdl.handle.net/1807/79382.
MLA Handbook (7th Edition):
Lopez Vasquez, Lucia. “Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line.” 2017. Web. 16 Jan 2021.
Vancouver:
Lopez Vasquez L. Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1807/79382.
Council of Science Editors:
Lopez Vasquez L. Assessment of Anti-α-Galactosidase A IgG Antibody Development in Fabry Disease Patients by ELISA and Purification of a Recombinant Human α-Galactosidase A from a Stable Overexpressing Human Cell Line. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79382

Northeastern University
10.
Thekkedath, Ritesh Vasudevan.
Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers.
Degree: PhD, School of Pharmacy, 2012, Northeastern University
URL: http://hdl.handle.net/2047/d20002485
► The use of lipid-based pharmaceutical nanocarriers, such as lipid-core polymeric micelles and liposomes have improved the pharmacokinetic and pharmacodynamic properties of many pharmaceuticals, especially in…
(more)
▼ The use of lipid-based pharmaceutical nanocarriers, such as lipid-core polymeric micelles and liposomes have improved the pharmacokinetic and pharmacodynamic properties of many pharmaceuticals, especially in chemotherapy. These delivery systems have not only helped in increasing the solubility of poorly soluble chemotherapeutic drugs but have also acted as reservoir of large molecular weight active pharmaceutical ingredients (API) like proteins. The objective of the thesis was to explore surface modification options to further enhance the delivery of pro-apoptotic small molecules for cell-specific delivery and proteins for intracellular delivery. The thesis has been divided into two sections.
Subjects/Keywords: Cancer; immunomicelles; lysosomal storage disease; lysosomotropic liposomes; TRAIL-micelles; VPRIV; Pharmacy and Pharmaceutical Sciences
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Thekkedath, R. V. (2012). Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/d20002485
Chicago Manual of Style (16th Edition):
Thekkedath, Ritesh Vasudevan. “Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers.” 2012. Doctoral Dissertation, Northeastern University. Accessed January 16, 2021.
http://hdl.handle.net/2047/d20002485.
MLA Handbook (7th Edition):
Thekkedath, Ritesh Vasudevan. “Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers.” 2012. Web. 16 Jan 2021.
Vancouver:
Thekkedath RV. Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers. [Internet] [Doctoral dissertation]. Northeastern University; 2012. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/2047/d20002485.
Council of Science Editors:
Thekkedath RV. Development of cell-specific and organelle-specific delivery systems by surface modification of lipid-based pharmaceutical nanocarriers. [Doctoral Dissertation]. Northeastern University; 2012. Available from: http://hdl.handle.net/2047/d20002485

IUPUI
11.
Conway, Betsy Ann.
The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models.
Degree: 2015, IUPUI
URL: http://hdl.handle.net/1805/7979
► Indiana University-Purdue University Indianapolis (IUPUI)
Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking…
(more)
▼ Indiana University-Purdue University Indianapolis (IUPUI)
Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking down glycogen to glucose within the lysosomes. PD cells accumulate massive quantities of glycogen within their lysosomes, and as such, PD is classified as a “lysosomal storage disease” (LSD). GAA-deficient cells also exhibit accumulation of autophagic debris. Symptoms of severe infantile PD include extreme muscle weakness, hypotonia, and hypertrophic cardiomyopathy, resulting in death before one year of age.
Certain LSDs are currently being successfully treated with enzyme replacement therapy (ERT), which involves intravenous infusion of a recombinant enzyme to counteract the endogenous deficiency. ERT has been less successful in PD, however, due to ineffective delivery of the recombinant enzyme. Alternatively, specific genes deletion may reduce lysosomal glycogen load, and could thus be targeted in PD therapy development. Absence of malin (EPM2B) or laforin (EPM2A) has been proposed to impair autophagy, which could reduce lysosomal glycogen levels. Additionally, deficiency of Stbd1 has been postulated to disable lysosomal glycogen import. Furthermore, Ptg deficiency was previously reported to abrogate Lafora body formation and correct neurological abnormalities in Lafora disease mouse models and could have similar effects on PD pathologies.
The goal of this study was to characterize the effects of homozygous disruption of Epm2a, Epm2b, Stbd1, and Ptg loci on total glycogen levels in PD mouse model heart tissue, as in severe infantile PD, it is accumulation of glycogen in the heart that results in fatal hypertrophic cardiomyopathy. Gaa-/- mice were intercrossed with Epm2a-/-, Epm2b-/-, Stbd1-/-, and Ptg-/- mice to generate wildtype (WT), single knockout, and double knockout mice. The results indicated that Gaa-/- hearts accumulated up to 100-fold more glycogen than the WT. These mice also displayed cardiac hypertrophy. However, deficiency of Epm2a, Epm2b, Stbd1, or PTG in the Gaa-/- background did not reveal changes of statistical significance in either heart glycogen or cardiac hypertrophy. Nevertheless, since total glycogen was measured, these deficiencies should not be discarded in future discussions of PD therapy, as increasing sample sizes and/or distinguishing cytosolic from lysosomal glycogen content may yet reveal differences of greater significance.
Advisors/Committee Members: Roach, Peter J., DePaoli-Roach, Anna, Hurley, Thomas.
Subjects/Keywords: Pompe disease; STBD1; PTG; EMP2A; EPM2B; Malin; Laforin; Lysosomal glycogen; GAA; Glycogen storage disease type II; Glycogen storage disease type II – Genetic aspects; Glycogen – Metabolism; Lysomal storage disease
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Conway, B. A. (2015). The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/7979
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Conway, Betsy Ann. “The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models.” 2015. Thesis, IUPUI. Accessed January 16, 2021.
http://hdl.handle.net/1805/7979.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Conway, Betsy Ann. “The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models.” 2015. Web. 16 Jan 2021.
Vancouver:
Conway BA. The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models. [Internet] [Thesis]. IUPUI; 2015. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1805/7979.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Conway BA. The effects of laforin, malin, Stbd1, and Ptg deficiencies on heart glycogen levels in Pompe disease mouse models. [Thesis]. IUPUI; 2015. Available from: http://hdl.handle.net/1805/7979
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
12.
Rouvière, Laura.
Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?.
Degree: Docteur es, Génétique, 2017, Sorbonne Paris Cité
URL: http://www.theses.fr/2017USPCB052
► La maladie de Sandhoff est une maladie génétique rare due à des mutations du gène HEXB. Elle se caractérise par un double déficit en hexosaminidase…
(more)
▼ La maladie de Sandhoff est une maladie génétique rare due à des mutations du gène HEXB. Elle se caractérise par un double déficit en hexosaminidase A (αβ) et B (ββ), responsable d’une accumulation de ganglioside GM2 essentiellement dans le système nerveux central (SNC). Cliniquement, la maladie débute dès les premiers mois de vie et le décès survient vers l’âge de 3 ans. A ce jour, aucun traitement n’est disponible pour cette maladie. Le modèle murin obtenu par invalidation du gène Hexb est un bon outil pour le développement d’approches thérapeutiques, car il présente un phénotype proche de la maladie humaine. Le but principal de mon projet de thèse était d’explorer une approche de transfert de gène dans le modèle murin de la maladie de Sandhoff en utilisant un vecteur scAAV9. Ce vecteur a la particularité de pouvoir traverser la barrière hématoencéphalique et de transduire le SNC après administration intraveineuse (IV). Un vecteur codant la chaîne β des hexosaminidases, appelé scAAV9-Hexb, a précédemment été administré par voie IV à des souris en période néonatale à une dose de 3,5 x 1013 vg/kg. Les souris traitées ont survécu comme les souris normales (>700 jours) sans développer d’atteinte neurologique, ni périphérique alors que les souris Sandhoff non traitées sont décédées vers l’âge de 4 mois. J’ai réalisé toutes les analyses à long terme des souris traitées en utilisant des tests de comportements, ainsi que des analyses tissulaires 24 mois après le traitement. Une analyse lipidique par HPTLC a montré que la surcharge en ganglioside GM2 est totalement absente au niveau du cerveau (4 mois après l'injection), alors que dans le cervelet cette accumulation est non significative, mais pas totalement absente. Aucun symptôme lié à cette surcharge n’a été mis en évidence chez les souris à 24 mois, mais nous nous sommes posé la question d’un possible effet délétère à long terme en cas d’extrapolation à la clinique. Nous avons donc décidé de tester une double administration IV + ICV (intracérébroventriculaire) en utilisant le même vecteur et la même dose globale de façon à mieux corriger le cervelet. Deux groupes de souris ont été injectés en période néonatale en utilisant des doses différentes dans les deux compartiments. Les analyses ont montré que dans le cerveau, à court terme, la restauration de l’activité enzymatique est partielle, mais significative. Par ailleurs, il existe une absence totale de surcharge en GM2, ainsi qu’une correction des biomarqueurs associés à la maladie. Dans le cervelet, l’efficacité du traitement a été montrée seulement pour le groupe traité avec la dose la plus importante en ICV, ce qui suggère qu’une dose minimale en ICV est nécessaire pour atteindre de manière globale le SNC. Ces résultats ont été confirmés par l’analyse à long terme. Concernant le foie, nos résultats ont montré qu’une dose IV minimale est nécessaire pour obtenir une baisse de l’accumulation lipidique. Ce travail a permis de définir les doses minimales nécessaires dans chaque compartiment (IV et ICV) et il montre que la…
Advisors/Committee Members: Caillaud, Catherine (thesis director).
Subjects/Keywords: Maladie lysosomale; AAV9; Thérapie génique; Maladie de Sandhoff; Lysosomal storage disease; AAV9; Gene therapy; Sandhoff disease; 616.042
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Rouvière, L. (2017). Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?. (Doctoral Dissertation). Sorbonne Paris Cité. Retrieved from http://www.theses.fr/2017USPCB052
Chicago Manual of Style (16th Edition):
Rouvière, Laura. “Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?.” 2017. Doctoral Dissertation, Sorbonne Paris Cité. Accessed January 16, 2021.
http://www.theses.fr/2017USPCB052.
MLA Handbook (7th Edition):
Rouvière, Laura. “Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?.” 2017. Web. 16 Jan 2021.
Vancouver:
Rouvière L. Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?. [Internet] [Doctoral dissertation]. Sorbonne Paris Cité; 2017. [cited 2021 Jan 16].
Available from: http://www.theses.fr/2017USPCB052.
Council of Science Editors:
Rouvière L. Transfert de gènes dans un modèle murin de la maladie de Sandhoff à l'aide d'un vecteur scAAV9 : intérêt d'une double voie d'administration ? : Gene transfer in murine model of Sandhoff disease using a scAAV9 vector : interest of double way of administration ?. [Doctoral Dissertation]. Sorbonne Paris Cité; 2017. Available from: http://www.theses.fr/2017USPCB052

University of Oxford
13.
Al Eisa, Nada.
Evaluation of new therapies in Niemann-Pick type C disease.
Degree: PhD, 2014, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:1538a0d6-b08e-444c-900d-de3ea3834ca5
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658481
► Niemann Pick type C (NPC) disease is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes.…
(more)
▼ Niemann Pick type C (NPC) disease is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes. The functions of the proteins these genes encode are not fully understood, but are thought to be involved in free cholesterol egress from the acidic compartment. The pathogenic cascade in proposed to begin with sphingosine accumulation followed by reduction of acidic store calcium levels. This results in impairing intracellular trafficking and storage of multiple lipid substrates in the late endosome/lysosomal compartment. In this thesis, multiple potential therapies have been tested in a mouse model of NPC1 disease including neuroprotective compounds. Positive effects were observed with some compounds, as reflected by increased life span and/or improved neurological function. In the course of these studies, I discovered another factor that affects the outcome of treatment with liver metabolised drugs. In the NPC1 mouse the cytochrome P450 system is impaired as is the case in the NPC1 cats and in patients. This thesis therefore sheds light on the impairment of this system at the genetic and functional level and presents data on why this aspect of pathology must be considered when designing therapeutics for this fatal neurodegenerative disease. This defect was partially corrected with bile acid supplementation, resulting in an unexpected functional improvement suggesting benefit in the CNS. Another aspect of NPC disease investigated was Crohn's-like intestinal inflammation that occurs in some NPC patients. This has been investigated in the Npc1-/- mouse model using two colitis models showing a partial protection by the Npc1 mutation with different infection kinetics and secretory cytokine profiles. Taken together, this thesis therefore provides insights into two novel aspects of pathogenesis (Crohn's-like intestinal inflammation and a drug metabolism defect) and provides new leads on treatments that target unique aspects of the pathogenic cascade.
Subjects/Keywords: 616.3; Medical sciences; Pharmacology; Life Sciences; Biochemistry; Niemann-Pick type C; Lysosomal storage disease; Inflammatory bowel disease
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Al Eisa, N. (2014). Evaluation of new therapies in Niemann-Pick type C disease. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:1538a0d6-b08e-444c-900d-de3ea3834ca5 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658481
Chicago Manual of Style (16th Edition):
Al Eisa, Nada. “Evaluation of new therapies in Niemann-Pick type C disease.” 2014. Doctoral Dissertation, University of Oxford. Accessed January 16, 2021.
http://ora.ox.ac.uk/objects/uuid:1538a0d6-b08e-444c-900d-de3ea3834ca5 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658481.
MLA Handbook (7th Edition):
Al Eisa, Nada. “Evaluation of new therapies in Niemann-Pick type C disease.” 2014. Web. 16 Jan 2021.
Vancouver:
Al Eisa N. Evaluation of new therapies in Niemann-Pick type C disease. [Internet] [Doctoral dissertation]. University of Oxford; 2014. [cited 2021 Jan 16].
Available from: http://ora.ox.ac.uk/objects/uuid:1538a0d6-b08e-444c-900d-de3ea3834ca5 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658481.
Council of Science Editors:
Al Eisa N. Evaluation of new therapies in Niemann-Pick type C disease. [Doctoral Dissertation]. University of Oxford; 2014. Available from: http://ora.ox.ac.uk/objects/uuid:1538a0d6-b08e-444c-900d-de3ea3834ca5 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658481

University of Toronto
14.
Ramsubir, Shobha.
Retrovirus-mediated Gene Therapy For Farber Disease.
Degree: 2008, University of Toronto
URL: http://hdl.handle.net/1807/11249
► Farber disease is a rare lysosomal storage disease (LSD) caused by a deficiency of acid ceramidase (AC). Patients show a classic triad of symptoms including…
(more)
▼ Farber disease is a rare lysosomal storage disease (LSD) caused by a deficiency of acid ceramidase (AC). Patients show a classic triad of symptoms including subcutaneous granulomas, laryngeal involvement and painful swollen joints. The most common and severe form has neurological manifestations and patients typically die by the age of two. Current treatment consists of symptomatic supportive care and allogeneic bone marrow transplantation (BMT). However, BMT has shown limited success. Gene therapy has previously been shown to be a promising treatment strategy for monogenetic diseases and has the potential to treat the underlying cause of the disease. Presented here is the first report of in vivo testing of retrovirus-mediated gene therapy strategies for the treatment of Farber disease. Retroviral vectors were engineered to overexpress AC and a cell surface marker, human CD25. Transduction with these viral vectors corrected the enzymatic defect in Farber patient cells and in vivo administration of the lentiviral vector led to long-term expression of the marking transgene as well as increased AC expression in the liver. To determine the effect of over-expression of AC, human CD34+ cells were transduced and transplanted into NOD/SCID animals. It was found that transgene-expressing cells could reconstitute the host. To address the neurological manifestations of Farber disease, vascular endothelial growth factor (VEGF) was investigated as an agent to transiently open the blood brain barrier for entry of lentivirus. It was found that in addition to increasing the amount of therapeutic virus in the brain, VEGF treatment also increased transduction in other organs. Further, to address the concerns of insertional mutagenesis associated with using integrating vectors, an immunotoxin-based strategy was developed as a safety system to clear transduced cells. It was found that a CD25-targeted immunotoxin could eliminate both transduced hematopoietic cells as well as tumor cells over-expressing CD25. This strategy can be employed following gene therapy should an unwanted proliferative event occur. Together, these studies represent considerable advances towards the development of a cure for Farber disease, demonstrating both therapeutic potential and also containing a built-in safety system.
PhD
Advisors/Committee Members: Medin, Jeffrey A., Medical Biophysics.
Subjects/Keywords: Gene Therapy; Lysosomal Storage Disease; Farber Disease; Retrovirus; 0786
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ramsubir, S. (2008). Retrovirus-mediated Gene Therapy For Farber Disease. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/11249
Chicago Manual of Style (16th Edition):
Ramsubir, Shobha. “Retrovirus-mediated Gene Therapy For Farber Disease.” 2008. Doctoral Dissertation, University of Toronto. Accessed January 16, 2021.
http://hdl.handle.net/1807/11249.
MLA Handbook (7th Edition):
Ramsubir, Shobha. “Retrovirus-mediated Gene Therapy For Farber Disease.” 2008. Web. 16 Jan 2021.
Vancouver:
Ramsubir S. Retrovirus-mediated Gene Therapy For Farber Disease. [Internet] [Doctoral dissertation]. University of Toronto; 2008. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1807/11249.
Council of Science Editors:
Ramsubir S. Retrovirus-mediated Gene Therapy For Farber Disease. [Doctoral Dissertation]. University of Toronto; 2008. Available from: http://hdl.handle.net/1807/11249

Washington University in St. Louis
15.
Shyng, Charles.
Infantile Batten Disease: Effective Therapy and Novel Model.
Degree: PhD, Biology & Biomedical Sciences (Molecular Cell Biology), 2016, Washington University in St. Louis
URL: https://openscholarship.wustl.edu/art_sci_etds/896
► Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten) is typically an early onset, neurodegenerative lysosomal storage disorder. INCL is caused by mutations to the gene…
(more)
▼ Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten) is typically an early onset, neurodegenerative
lysosomal storage disorder. INCL is caused by mutations to the gene CLN1 which codes for the
lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1). PPT1 is a soluble
lysosomal enzyme that functions to cleave fatty acyl chains from proteins destined for degradation. Deficiency in PPT1 leads to the accumulation of autofluorescent
storage material, a hallmark of the NCLs. The
storage material has been implicated in progressive histopathological changes in the brain such as neuronal loss, astrocytosis, microgliosis, and immune cell infiltration. These histopathological changes result in a progression of clinical signs including vision loss, decline in motor function, cognitive deficits, seizures, and premature death. Currently, there are no cures or treatments for INCL. However, a murine model of INCL has been used in pre-clinical therapy studies. The PPT1-/- mouse has been shown to be a reliable model for the human INCL
disease. Detailed temporal and spatial histopathological examinations of murine INCL in the brain have led to intracranial gene therapy studies. These pre-clinical studies have resulted in significant improvements in biochemical, histopathological, and functional deficits seen in the untreated PPT1-/- mouse. However, there have only been modest improvements in lifespan. Given the identification and development of improved gene therapy vectors, this was a surprising finding. Therefore, the first section of the dissertation, we pursued a more thorough characterization of the central nervous system to identify potential regions of
disease not targeted by intracranial gene therapy. We identified the spinal cord as a significant site of
disease that was not previously characterized or corrected. This allowed us to target both the brain and spinal cord with AAV-based gene therapy. We demonstrated that targeting the entirety of the central nervous system was necessary to treat INCL more effectively. From these and historical studies, we identified a multitude of cell types that are involved with INCL pathogenesis. In the central nervous system, INCL has been shown to progress sequentially from astrocytosis, to neuronal loss, to microgliosis and immune cell infiltration. PPT1 is ubiquitously expressed; therefore, its deficiency in INCL could lead to pathology in every cell type. Currently, we are unable to model cellular and metabolic changes in specific cell types in INCL due to ‘cross-correction’. While ‘cross-correction’ is beneficial for the development of therapeutics, it interferes with our ability to understand the role of PPT1 in specific cell types. Therefore, in the second section of the dissertation, we sought to determine the cell-autonomous nature of PPT1. Because PPT1 is a soluble
lysosomal hydrolase that can undergo ‘cross-correction’, we developed a chimeric enzyme whereby PPT1 is tethered to the
lysosomal membrane. We demonstrated that tethered PPT1 retains its enzymatic…
Advisors/Committee Members: Mark S. Sands, Daniel S. Ory, Steven J. Mennerick, David H. Gutmann, Jin-Moo Lee, John Cirrito.
Subjects/Keywords: Gene Therapy; Infantile Batten Disease; Lysosomal Storage Disorder; Neuronal Ceroid Lipofuscinosis; Palmitoyl-protein thioesterase-1; Rare Disease
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APA (6th Edition):
Shyng, C. (2016). Infantile Batten Disease: Effective Therapy and Novel Model. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/896
Chicago Manual of Style (16th Edition):
Shyng, Charles. “Infantile Batten Disease: Effective Therapy and Novel Model.” 2016. Doctoral Dissertation, Washington University in St. Louis. Accessed January 16, 2021.
https://openscholarship.wustl.edu/art_sci_etds/896.
MLA Handbook (7th Edition):
Shyng, Charles. “Infantile Batten Disease: Effective Therapy and Novel Model.” 2016. Web. 16 Jan 2021.
Vancouver:
Shyng C. Infantile Batten Disease: Effective Therapy and Novel Model. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2016. [cited 2021 Jan 16].
Available from: https://openscholarship.wustl.edu/art_sci_etds/896.
Council of Science Editors:
Shyng C. Infantile Batten Disease: Effective Therapy and Novel Model. [Doctoral Dissertation]. Washington University in St. Louis; 2016. Available from: https://openscholarship.wustl.edu/art_sci_etds/896

Victoria University of Wellington
16.
Heathcott, Rosemary.
Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models.
Degree: 2015, Victoria University of Wellington
URL: http://hdl.handle.net/10063/9084
► Heparan sulphate proteoglycans (HSPG) are central to numerous processes of the mammalian cell. The highly charged negative side chains of the heparan sulphate (HS) oligosaccharides…
(more)
▼ Heparan sulphate proteoglycans (HSPG) are central to numerous processes of the mammalian cell. The highly charged negative side chains of the heparan sulphate (HS) oligosaccharides are essential for the regulatory and structural functions of the proteoglycan. Synthetic HS compounds have potential therapeutic value due to their ability to mimic naturally occurring HS. Niemann-Pick
disease type C (NPC) is a fatal childhood neurodegenerative
disease with characteristic cholesterol and sphingolipid accumulation in the late endosome or lysosome. Alzheimer’s
disease, another neurodegenerative disorder, shares alterations of cholesterol and amyloid β metabolism with NPC. In this study,a set of novel heparan sulphate compounds with a range of structures and oligosaccharide side groups with a variety of degrees of sulphation was investigated with regards to their effects on cholesterol and amyloid β metabolism in cell line models of these two diseases. Fluorescent staining of cholesterol and confocal microscopy showed highly sulphated compounds reduce the accumulation of cholesterol in the perinuclear
lysosomal storage organelles in patient fibroblast cell lines. The compounds had no effect on secreted amyloid β levels or amyloid precursor protein levels in a neuronal cell line model of early onset Alzheimer’s
disease. The mechanism of cholesterol reduction is unclear but may be related to a reduction in HSPG-associated endocytosis of LDL/cholesterol.
Advisors/Committee Members: Munkacsi, Andrew.
Subjects/Keywords: Heparan sulphate; Cholesterol metabolism; Neurodegenerative disease; Alzheimer’s disease; Niemann-Pick type C; Lysosomal storage disorder; Heparan sulphate proteoglycan
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APA ·
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MLA ·
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APA (6th Edition):
Heathcott, R. (2015). Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/9084
Chicago Manual of Style (16th Edition):
Heathcott, Rosemary. “Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models.” 2015. Masters Thesis, Victoria University of Wellington. Accessed January 16, 2021.
http://hdl.handle.net/10063/9084.
MLA Handbook (7th Edition):
Heathcott, Rosemary. “Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models.” 2015. Web. 16 Jan 2021.
Vancouver:
Heathcott R. Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models. [Internet] [Masters thesis]. Victoria University of Wellington; 2015. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10063/9084.
Council of Science Editors:
Heathcott R. Heparan sulphate compounds regulate cholesterol metabolism in neurodegenerative disease models. [Masters Thesis]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/9084
17.
Guce, Abigail Ida.
Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.
Degree: PhD, Chemistry, 2010, U of Massachusetts : PhD
URL: https://scholarworks.umass.edu/open_access_dissertations/202
► Human α-galactosidase (α-GAL; EC 3.2.1.22) is a lysosomal enzyme that hydrolyzes of terminal alpha-linked galactosyl residue of glycosphingolipids. Deficiencies in α-GAL leads to Fabry…
(more)
▼ Human α-galactosidase (α-GAL; EC 3.2.1.22) is a
lysosomal enzyme that hydrolyzes of terminal alpha-linked galactosyl residue of glycosphingolipids. Deficiencies in α-GAL leads to Fabry
disease, which is characterized by the build-up of globotriaosylceramide and other neutral substrates in cells, ultimately leading to a multi-systemic organ failure in patients. Hundreds of distinct mutations have been found in the α-GAL gene of Fabry
disease patients. One current treatment for Fabry
disease is Enzyme Replacement Therapy (ERT), which restores the missing α-GAL function. An alternative treatment, called Pharmacological Chaperone Therapy (PCT), utilizes a small molecule substrate analogue, 1-deoxygalactonojirimycin (DGJ). In order to better understand molecular basis of Fabry
disease, this work addresses structural and mechanistic studies of the α-GAL glycoprotein. First, we have determined crystal structures of each stage in the catalytic mechanism of the α-GAL enzymatic reaction. These studies reveal a novel strained conformation of the sugar when it is covalently bound to the enzyme. Second, we examine the molecular mechanism of chaperoning by pharmacological chaperones. A combination of biochemical and biophysical approaches reveals that the high potency of the DGJ chaperone is due to an interaction with α-GAL residue D170. Third, we have investigated mutant α-GAL proteins for their response to pharmacological chaperones, leading to a set of structure-based rules for predicting the effect of pharmacological chaperone on every Fabry
disease patient. Fourth, we use rational design approaches to interconvert the specificity of α-GAL into that of a related enzyme, α-N-acetylgalactosaminidase (α-NAGAL). Structural and enzymatic experiments show that the engineered enzyme contains new substrate specificity, as predicted by the design. The structural and mechanistic details we present in this thesis provide better understanding of the catalysis of the human α-galactosidase enzyme as well as define the molecular basis for pharmacological chaperone therapy in Fabry patients. Since α-GAL is one of the best studied
lysosomal storage disease, it might be used as a model to better understand other
lysosomal storage diseases and as well as other diseases related to misfolded proteins, including Alzheimer's and Parkinson's diseases.
Advisors/Committee Members: Scott C. Garman.
Subjects/Keywords: Pharmacological chaperones; Galactosidase; Fabry disease; Lysosomal storage diseases; Chemistry
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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APA (6th Edition):
Guce, A. I. (2010). Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. (Doctoral Dissertation). U of Massachusetts : PhD. Retrieved from https://scholarworks.umass.edu/open_access_dissertations/202
Chicago Manual of Style (16th Edition):
Guce, Abigail Ida. “Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.” 2010. Doctoral Dissertation, U of Massachusetts : PhD. Accessed January 16, 2021.
https://scholarworks.umass.edu/open_access_dissertations/202.
MLA Handbook (7th Edition):
Guce, Abigail Ida. “Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones.” 2010. Web. 16 Jan 2021.
Vancouver:
Guce AI. Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. [Internet] [Doctoral dissertation]. U of Massachusetts : PhD; 2010. [cited 2021 Jan 16].
Available from: https://scholarworks.umass.edu/open_access_dissertations/202.
Council of Science Editors:
Guce AI. Structural and Mechanistic Studies of alpha-galactosidase A and Pharmacological Chaperones. [Doctoral Dissertation]. U of Massachusetts : PhD; 2010. Available from: https://scholarworks.umass.edu/open_access_dissertations/202

University of Michigan
18.
Yu, Ting.
Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention.
Degree: PhD, Molecular & Cellular Pathology, 2013, University of Michigan
URL: http://hdl.handle.net/2027.42/98048
► Niemann-Pick Type C disease (NPC) is a childhood-onset neurodegenerative disorder characterized by the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Most…
(more)
▼ Niemann-Pick Type C
disease (NPC) is a childhood-onset neurodegenerative disorder characterized by the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Most NPC cases are caused by loss-of-function mutations in the ubiquitously expressed NPC1 gene, which encodes a multi-pass transmembrane protein essential for mobilizing cholesterol from the endolysosomal system. How NPC1 dysfunction leads to progressive neurodegeneration remains unknown and effective treatment is lacking.
I used a conditional knockout mouse model of NPC to define the timing and cell type underlying neurodegeneration due to Npc1 deficiency. Global deletion of Npc1 in adult mice leads to progressive weight loss, impaired motor function and early death similar to that resulting from germline deletion. Additionally, the
disease can be recapitulated when Npc1 is specifically deleted in neurons. In contrast, Npc1 deficiency in mature astrocytes does not produce any detectable defects. These findings demonstrate that neurons, but not astrocytes, play a critical role in the pathogenesis of NPC.
I also explored the contribution of exogenously derived cholesterol to CNS myelination. I showed that Npc1 deficiency in either neurons or oligodendrocytes is sufficient to block oligodendrocyte maturation and myelination, with the most severe impairment in the forebrain. In addition, Npc1 deficiency in oligodendrocytes also leads to demyelination and secondary Purkinje neuron degeneration in aged mice. These data demonstrate that lipid uptake by neurons and oligodendrocytes through an Npc1-dependent pathway is required for both the formation and maintenance of CNS myelin.
In addition, I explored a potential treatment strategy that targets mutant NPC1 protein with missense mutations. My data demonstrate that by increasing ER calcium levels in patient fibroblasts, ryanodine receptor antagonists increase the steady-state levels of the NPC1 I1061T protein, promote its trafficking to the late endosomes and lysosomes, and recue the lipid
storage defects. My work highlights the utility of proteostasis regulators to remodel the ER protein folding environment to enable functional recovery. In summary, the findings presented here provide new insights into the pathogenic mechanisms underlying NPC and suggest a possible approach for therapeutic intervention.
Advisors/Committee Members: Lieberman, Andrew P. (committee member), Albin, Roger L. (committee member), Dressler, Gregory R. (committee member), Meisler, Miriam H. (committee member), Zochowska, Anuska A. (committee member).
Subjects/Keywords: Niemann-Pick Type C; Neurodegeneration; Lysosomal Storage Disease; Cell Autonomous; Myelin; Proteostasis; Genetics; Neurosciences; Pathology; Health Sciences
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Yu, T. (2013). Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/98048
Chicago Manual of Style (16th Edition):
Yu, Ting. “Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention.” 2013. Doctoral Dissertation, University of Michigan. Accessed January 16, 2021.
http://hdl.handle.net/2027.42/98048.
MLA Handbook (7th Edition):
Yu, Ting. “Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention.” 2013. Web. 16 Jan 2021.
Vancouver:
Yu T. Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention. [Internet] [Doctoral dissertation]. University of Michigan; 2013. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/2027.42/98048.
Council of Science Editors:
Yu T. Niemann-Pick Type C Disease: Molecular Mechanisms of Neurodegeneration and Targets for Therapeutic Intervention. [Doctoral Dissertation]. University of Michigan; 2013. Available from: http://hdl.handle.net/2027.42/98048

University of Washington
19.
Yi, Fan.
Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry.
Degree: PhD, 2018, University of Washington
URL: http://hdl.handle.net/1773/42237
► Chapter I. Development of Newborn Screening Method for Mucopolysaccharidosis III Type A in Dried Blood Spot using Tandem Mass Spectrometry Mucopolysaccharidosis III type A (MPS…
(more)
▼ Chapter I. Development of Newborn Screening Method for Mucopolysaccharidosis III Type A in Dried Blood Spot using Tandem Mass Spectrometry Mucopolysaccharidosis III type A (MPS III A) is an autosomal recessive inherited
disease with no current treatment available. It is caused by the deficiency of sulfamidase (SGSH) in the lysosome and the inability to degrade a polysaccharide called heparan sulfate. Gene therapy and enzyme replacement therapy for MPS III A are already in development and have shown promising preclinical result. To achieve the best result from the potential treatment, it is necessary to administrate the treatment before the onset of irreversible damage to the central nervous system. To fulfill this requirement, a simple, fast and robust method for screening MPS III A in newborns is in demand. The first high-throughput screening method for MPS III A that is compatible with dried blood spot (DBS) was developed. This method used a synthetic substrate to assay the enzyme activity in dried blood spots via tandem mass spectrometry (MS/MS). Preliminary data suggested that the newly developed assay was able to distinguish patients from normal population in sulfamidase activity: patient SGSH activity ranged from 0.013 – 0.056 μmol/h/L; while normal newborn SGSH activity ranged from 0.10 - 0.81 μmol/h/L. Chapter II. Development of Newborn Screening Method for Mucopolysaccharidosis III Type B in Dried Blood Spot using Tandem Mass Spectrometry Mucopolysaccharidosis III type B (MPS III B) is an autosomal recessive inherited
disease with no current treatment. It is caused by the deficiency of N-acetyl glucosaminidase (NAGLU) in the lysosome and the inability to degrade a polysaccharide called heparan sulfate. NAGLU is a downstream enzyme of sulfamidase, which causes MPS III A. Sulfamidase and NAGLU are working together with several other enzymes, acetyl-CoA: α-glucosaminide acetyltransferase and N-acetylglucosamine 6-sulfatase, to cleave off the nonreducing end glucosamine residue from a heparan sulfate polysaccharide molecule. The accumulation of heparan sulfate in the lysosome will cause damage to the central nervous system which in turn will result in mild somatic and severe neurological manifestation. It is crucial to identify the affected individual as soon as possible, preferably right after birth. In order to do so, a high-throughput screening method was developed, and it had shown its power in distinguish patients from the normal people. Preliminary data suggested that a random normal person has a NAGLU activity 100 times higher than the one of the affected persons.
Advisors/Committee Members: Gelb, Michael H (advisor).
Subjects/Keywords: Dried blood spots; Lysosomal storage disease; Mucopolysaccharidosis III A and B; Newborn screening; Tandem Mass Spectrometry; Chemistry; Chemistry
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Yi, F. (2018). Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/42237
Chicago Manual of Style (16th Edition):
Yi, Fan. “Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry.” 2018. Doctoral Dissertation, University of Washington. Accessed January 16, 2021.
http://hdl.handle.net/1773/42237.
MLA Handbook (7th Edition):
Yi, Fan. “Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry.” 2018. Web. 16 Jan 2021.
Vancouver:
Yi F. Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry. [Internet] [Doctoral dissertation]. University of Washington; 2018. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1773/42237.
Council of Science Editors:
Yi F. Development of Newborn Screening Methods for Mucopolysaccharidosis III type A and type B in Dried Blood Spot using Tandem Mass Spectrometry. [Doctoral Dissertation]. University of Washington; 2018. Available from: http://hdl.handle.net/1773/42237
20.
Havelaar, Adrie.
Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease.
Degree: 1999, Erasmus University Medical Center
URL: http://hdl.handle.net/1765/15789
Subjects/Keywords: acid storage diseases; genetic disease; lysosomal disorders
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Havelaar, A. (1999). Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/15789
Chicago Manual of Style (16th Edition):
Havelaar, Adrie. “Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease.” 1999. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 16, 2021.
http://hdl.handle.net/1765/15789.
MLA Handbook (7th Edition):
Havelaar, Adrie. “Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease.” 1999. Web. 16 Jan 2021.
Vancouver:
Havelaar A. Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 1999. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/1765/15789.
Council of Science Editors:
Havelaar A. Lysosomal Membrane Transport Proteins and their Significance in Human Genetic Disease. [Doctoral Dissertation]. Erasmus University Medical Center; 1999. Available from: http://hdl.handle.net/1765/15789

Universidade do Rio Grande do Sul
21.
Camelier, Marli Teresinha Viapiana.
Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas.
Degree: 2016, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/150661
► Introdução: As Doenças lisossômicas (DLs) são condições genéticas, herdadas na sua maioria de forma autossômica recessiva, caracterizadas usualmente pela deficiência de enzimas lisossômicas específicas, envolvidas…
(more)
▼ Introdução: As Doenças lisossômicas (DLs) são condições genéticas, herdadas na sua maioria de forma autossômica recessiva, caracterizadas usualmente pela deficiência de enzimas lisossômicas específicas, envolvidas na síntese, degradação, armazenamento ou transporte de macromoléculas necessárias para o funcionamento normal do organismo. Nas situações mais típicas, o substrato não degradado acumula-se progressivamente nos lisossomos, com repercussões estruturais e funcionais, levando a sinais e sintomas característicos. Os pacientes apresentam um amplo espectro de manifestações clínicas, que podem incluir disfunção de órgãos, anormalidades esqueléticas, envolvimento neuronal, entre outras. O diagnóstico é usualmente obtido pela identificação da deficiência enzimática específica em leucócitos obtidos do sangue periférico, usualmente realizado em laboratórios de referência. O transporte da amostra pode ser um obstáculo quando o serviço requisitante está situado longe do centro de referência ou em outro país, situação em que a amostra de sangue pode chegar ao laboratório já sem condições de ser analisada. Objetivo: Este estudo teve como objetivo principal, tornar disponível um método mais simples, seguro e acessível que utiliza amostras de leucócitos impregnados em papel filtro (LIPF) como uma nova ferramenta para o diagnóstico bioquímico de pacientes com DLs. Métodos: O estudo envolveu amostras de pacientes com diagnóstico previamente confirmado de DLs (amostra de conveniência, por se tratarem de doenças raras, com incidências individuais ao redor de 1:100.000 recém-nascidos vivos). Foram incluídos no estudo os pacientes com diagnóstico já estabelecido de DLs selecionadas (MPS IVA, Doença de Krabbe, Doença de Gaucher e Doença de Pompe), independente do sexo e/ou idade, atendidos no Serviço de Genética Médica do HCPA, que concordaram em participar do estudo. O grupo de referência negativo foi constituído pelas amostras de 50 indivíduos hígidos, adultos, de ambos os sexos. Resultados: Os resultados obtidos nos ensaios enzimáticos de pacientes com MPS IVA, Doença de Krabbe, Doença de Gaucher e Doença de Pompe, indicaram que as enzimas analisadas em amostras de LIPF permitiram a identificação de todos os pacientes, com sensibilidade de 100%. Os testes de estabilidade realizados nas amostras de LIPF indicaram que as amostras, quando mantidas a 4ºC, se mostram estáveis por pelo menos 30 dias. Conclusões: Nas condições utilizadas, amostras de LIPF se mostraram adequadas para a identificação segura de pacientes com MPS tipo IVA, Doença de Krabbe, Doença de Gaucher e Doença de Pompe. As amostras de leucócitos secos em papel filtro são mais estáveis e seguras para o transporte, indicando que possa ser esta uma importante ferramenta para facilitar a identificação de pacientes com DLDs, especialmente daqueles que vivem em áreas que tem dificuldades para a remessa de amostras líquidas para serviços de referência.
Background: Lysosomal Disorders (LDs) are genetic conditions, mostly inherited in autosomal recessive fashion, usually…
Advisors/Committee Members: Giugliani, Roberto.
Subjects/Keywords: Erros inatos do metabolismo; Lysosomal storage disorders; Mucopolissacaridoses; MPS IVA; Leucodistrofia de células globóides; Krabbe disease; Doença de Gaucher; Gaucher’s disease; Pompe disease; Doença de depósito de glicogênio tipo II; Blood impregnated on filter paper; Lysosomal enzymes
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Camelier, M. T. V. (2016). Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/150661
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Camelier, Marli Teresinha Viapiana. “Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas.” 2016. Thesis, Universidade do Rio Grande do Sul. Accessed January 16, 2021.
http://hdl.handle.net/10183/150661.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Camelier, Marli Teresinha Viapiana. “Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas.” 2016. Web. 16 Jan 2021.
Vancouver:
Camelier MTV. Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2016. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10183/150661.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Camelier MTV. Avaliação do uso de amostras de leucócitos impregnados em papel filtro para o diagnóstico de doenças lisossômicas. [Thesis]. Universidade do Rio Grande do Sul; 2016. Available from: http://hdl.handle.net/10183/150661
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Lincoln University
22.
Xu, Janet Boyu.
Cell biology and biochemical studies of ovine batten disease.
Degree: 2018, Lincoln University
URL: http://hdl.handle.net/10182/10185
► The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited neurodegenerative lysosomal storage diseases of humans, which result in severe cortical atrophy,…
(more)
▼ The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited neurodegenerative lysosomal storage diseases of humans, which result in severe cortical atrophy, blindness, seizures, and the accumulation of fluorescent lysosome-derived organelles in neurons and most other cells throughout the body. Two naturally occurring of forms of NCL in sheep, CLN5 and CLN6, are used to study human disorders. A mutation in a soluble lysosomal protein (CLN5) causes NCL in Borderdale sheep and the South Hampshire sheep have a defective intracellular endoplasmic reticulum membrane protein (CLN6). The functions of these proteins are still unclear. Generation of highly specific and sensitive antibodies to these proteins would be very useful for biological and functional studies. Studies described in this thesis used ovine CLN5 and CLN6 NCL models to establish the full length coding sequences of the genes and expression of the encoded proteins. Antibodies against ovine CLN5 and CLN6 were generated and used for characterisation studies of both proteins in vitro.
The full length ovine CLN5 gene sequence was amplified using a two-step PCR and ligation strategy with internal overhanging primers. Ovine CLN5 exon 1 has an allelic variant, but it was not associated with the CLN5 sheep mutation. Recombinant ovine CLN5 and CLN6 proteins were not expressed in Escherichia coli (E. coli) prokaryotic systems, perhaps because the gene sequences may be toxic to the host.
Recombinant ovine CLN5 and CLN6 proteins were expressed successfully in eukaryotic mammalian cells using lentiviral vectors. The adenoviral antibodies against ovine CLN5 and CLN6 specifically recognized ovine CLN5 and CLN6 as shown by immunocytochemistry, Western blotting and mass spectrometry. The rabbit anti-CLN5 antibodies specifically identified the ovine mature CLN5 glycosylated form with a molecular weight of 60 kDa in media and cells and a molecular weight of 35 kDa when deglycosylated by PNGase F. The rabbit anti-CLN6 antibodies specifically detected overexpressed ovine CLN6 at molecular weight of 27 kDa in cells by Western blotting. Mass spectrometry revealed that the CLN5 N-signal sequence is cleaved off when it is mature. The deglycosylation study confirmed that CLN5 is a soluble glycosylated protein, containing high-mannose or complex type glycans at six out of eight predicted N-glycosylation sites.
A lysosomal localisation of ovine CLN5 study was confirmed by rabbit anti-CLN5 antibodies labelling of the cells that also expressed the lysosomal associated membrane protein LAMP1, while ER intracellular localisation of ovine CLN6 was revealed by co-staining with rabbit anti-CLN6 antibodies and an ER marker. The CLN5 antibodies also detected endogenous CLN5 expression throughout the normal sheep and human brains. This study also provides evidence for the hypothesis of interactions between CLN5 and CLN6 in cultured and virally transduced neural cell lines using the anti-CLN5 and anti-CLN6 antibodies. Co-expression of CLN6 and CLN5 up-regulated…
Subjects/Keywords: Batten disease; neuronal ceroid lipofuscinosis; lysosomal storage disease; animal models; sheep; brain; CLN5; CLN6; proteins; antibodies; 060108 Protein Trafficking; 070709 Veterinary Pathology; 110903 Central Nervous System
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APA ·
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APA (6th Edition):
Xu, J. B. (2018). Cell biology and biochemical studies of ovine batten disease. (Thesis). Lincoln University. Retrieved from http://hdl.handle.net/10182/10185
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Xu, Janet Boyu. “Cell biology and biochemical studies of ovine batten disease.” 2018. Thesis, Lincoln University. Accessed January 16, 2021.
http://hdl.handle.net/10182/10185.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Xu, Janet Boyu. “Cell biology and biochemical studies of ovine batten disease.” 2018. Web. 16 Jan 2021.
Vancouver:
Xu JB. Cell biology and biochemical studies of ovine batten disease. [Internet] [Thesis]. Lincoln University; 2018. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10182/10185.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Xu JB. Cell biology and biochemical studies of ovine batten disease. [Thesis]. Lincoln University; 2018. Available from: http://hdl.handle.net/10182/10185
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

McMaster University
23.
Abou-Ouf, Hatem A.
TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY.
Degree: PhD, 2013, McMaster University
URL: http://hdl.handle.net/11375/15264
► Abstract Sandhoff disease (SD) is a monogenic lysosomal storage disorder caused by a lack of a functional β-subunit of the beta-hexosaminidase A and B…
(more)
▼ Abstract Sandhoff disease (SD) is a monogenic lysosomal storage disorder caused by a lack of a functional β-subunit of the beta-hexosaminidase A and B enzymes. The clinical phenotype of Hexb-/-mouse model recapitulates the symptoms and signs of Tay-Sachs and Sandhoff diseases in human. To gain insight into the neuropathology of Sandhoff disease, we defined the role of TNFα in the development and progression of Sandhoff disease pathology in mice, by generating a <em>Hexb-/-Tnf</em>a<em>-/-</em> double knock-out mouse. Behavioural testing and immunostaining data revealed the neurodegenerative role of TNFα in disease pathology. Double knock-out mice showed ameliorated clinical course, with prolonged life span. TNFα-deficient Sandhoff mice also demonstrate decreased levels of astrogliosis, and reduced neuronal cell death. Deletion of Tnfα in Sandhoff mice inhibited JAK2/STAT3 pathway, implicating its role in glia cell activation. This result points to TNFa as a potential therapeutic target to attenuate neuro-pathogenesis. To investigate whether blood-derived or CNS-derived TNFα has the major impact on neurological function, we transplanted <em>Hexb-/-Tnfα+/+</em> with bone marrow from either <em>Hexb-/-Tnfα-/-</em>or <em>Hexb-/-Tnf</em>a<em>+/+</em> mice donors. Neurological tests shows a significant clinical improvement for Hexb<em>-/-Tnfα-/-</em> compared to <em>Hexb-/-Tnf</em>a<em>+/+</em> recipient, regardless the genotype of donor cells. These findings highlight the importance of resident-derived TNFα during the robust neurodegenerative consequences in Sandhoff disease. To understand of the role of microRNAs in Sandhoff pathology, we investigated the miRNA profile in Sandhoff brains. A pattern of dys-regulated microRNAs was evident in Sandhoff CNS. Microarray identified miR-210 and miR-96 dys-regulated pattern in the CNS of Sandhoff mice. Strikingly, neuronal pentraxin, a putative target gene for miR-210, was induced in Sandhoff brains. Taken together, this work establishes the proinflammatory role of TNFα in Sandhoff pathology, leading to massive neuro-apoptosis. Importantly, our studies propose that neuronal pentraxin as a novel target gene for microRNA-210 in Sandhoff brain samples, providing a potential modulator of neurodegeneration.
Doctor of Philosophy (PhD)
Advisors/Committee Members: Igdoura, Suleiman A., Nurse, Colin A., Biology.
Subjects/Keywords: Neurodegeneration; Sandhoff disease; Lysosomal storage disease; Tumor Necrosis Factor alpha (TNF); MicroRNA; Bone Marrow Transplantation (BMT); Biology; Genetics; Medical Genetics; Medical Molecular Biology; Medical Neurobiology; Molecular genetics; Neurosciences; Biology
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Abou-Ouf, H. A. (2013). TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/15264
Chicago Manual of Style (16th Edition):
Abou-Ouf, Hatem A. “TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY.” 2013. Doctoral Dissertation, McMaster University. Accessed January 16, 2021.
http://hdl.handle.net/11375/15264.
MLA Handbook (7th Edition):
Abou-Ouf, Hatem A. “TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY.” 2013. Web. 16 Jan 2021.
Vancouver:
Abou-Ouf HA. TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY. [Internet] [Doctoral dissertation]. McMaster University; 2013. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/11375/15264.
Council of Science Editors:
Abou-Ouf HA. TUMOR NECROSIS FACTOR ALPHA (TNFα) in SANDHOFF DISEASE PATHOLOGY. [Doctoral Dissertation]. McMaster University; 2013. Available from: http://hdl.handle.net/11375/15264

University of Manchester
24.
Langford-Smith, Alexander William Walker.
Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA.
Degree: PhD, 2012, University of Manchester
URL: https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html
;
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570252
► Mucopolysaccharidosis type III (Sanfilippo) is comprised of four phenotypically similar lysosomal storage disorders (MPS IIIA-D) caused by the deficiency of enzymes that catabolise heparan sulphate…
(more)
▼ Mucopolysaccharidosis type III (Sanfilippo) is comprised of four phenotypically similar lysosomal storage disorders (MPS IIIA-D) caused by the deficiency of enzymes that catabolise heparan sulphate (HS). Progressive accumulation of HS results in abnormal behaviour, progressive cognitive and motor impairment and death in mid-teens. There are currently no treatments for MPS III. To assess the effect of novel therapeutics in the mouse models of MPS III it is necessary to examine the effect on primary storage of HS, secondary storage and behaviour. The reported behaviour of MPS IIIA and B mice is conflicting therefore we developed a one-hour open field test, performed at the same time of day during a period of hyperactivity observed in a previous circadian rhythm study of MPS IIIB mice. At 8 months of age MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and a reduction in immobility time. The MPS IIIA mice presented with the same behavioural phenotype as the MPS IIIB mice and were significantly hyperactive at 4 and 6 months of age and also displayed a reduced sense of danger. The hyperactivity and reduced sense of danger observed in the mice is consistent with the patient phenotype. Whilst haematopoietic stem cell transplant (HSCT) is the standard therapy used to treat the similar HS storage disorder MPS I Hurler, it is ineffectual in MPS IIIA. We hypothesise that HSCT failure in MPS IIIA is due to insufficient enzyme production in the brain by donor-derived microglial cells. By increasing expression of N-sulphoglucosamine sulphohydrolase (SGSH) we may be able to treat MPS IIIA. Therefore we compared the effect of HSCT using normal haematopoietic stem cells (WT-HSCT) to lentiviral overexpression of SGSH in normal cells (LV-WT-HSCT) or MPS IIIA cells (LV-IIIA-HSCT) in MPS IIIA mice, using the behavioural tests developed.SGSH activity in the brain of MPS IIIA recipients was not significantly increased by WT-HSCT, but was significantly increased by LV-IIIA-HSCT and LV-WT-HSCT. HS was significantly reduced by all transplants but the best treatment was LV-WT-HSCT. Neuroinflammation, indicated by the number of microglia in the brain, was significantly reduced by all treatments but remains significantly elevated. GM2 gangliosides were significantly reduced by WT-HSCT and LV-WT-HSCT and were no longer significantly elevated, but LV-IIIA-HSCT had no significant effect. Critically LV-WT-HSCT corrected the behaviour at 4 and 6 months of age whilst the other treatments had no significant effect. LV-WT-HSCT and WT-HSCT reduced GM2 gangliosides and neuroinflammation equally but only LV-WT-HSCT corrected behaviour and primary HS storage, suggesting they are the important factors in MPS IIIA pathology. LV-WT-HSCT corrects the neurological phenotype in MPS IIIA mice and is a clinically viable approach to treat MPS IIIA and other neuropathic lysosomal storage disorders.
Subjects/Keywords: 616.8; Lysosomal Storage Disorder; Lysosomal Storage Disease; LSD; Mucopolysaccharidosis; MPS; Mucopolysaccharidosis type IIIA; MPS IIIA; Sanfilippo; Sanfilippo type A; Haematopoietic Stem Cell; Lentiviral Vector; Gene Therapy; Stem Cell Gene Therapy; Behaviour; Open Field
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Langford-Smith, A. W. W. (2012). Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570252
Chicago Manual of Style (16th Edition):
Langford-Smith, Alexander William Walker. “Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA.” 2012. Doctoral Dissertation, University of Manchester. Accessed January 16, 2021.
https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570252.
MLA Handbook (7th Edition):
Langford-Smith, Alexander William Walker. “Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA.” 2012. Web. 16 Jan 2021.
Vancouver:
Langford-Smith AWW. Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA. [Internet] [Doctoral dissertation]. University of Manchester; 2012. [cited 2021 Jan 16].
Available from: https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570252.
Council of Science Editors:
Langford-Smith AWW. Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA. [Doctoral Dissertation]. University of Manchester; 2012. Available from: https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570252

Universidade do Rio Grande do Sul
25.
Turcatel, Elias.
Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática.
Degree: 2015, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/129765
► A doença de Gaucher (DG) é uma doença de armazenamento lisossômico causada por uma mutação no gene que codifica a enzima β-glicosidase, a deficiência dessa…
(more)
▼ A doença de Gaucher (DG) é uma doença de armazenamento lisossômico causada por uma mutação no gene que codifica a enzima β-glicosidase, a deficiência dessa enzima provoca o acúmulo de glicosilceramidas nos lisossomos do sistema retículo endotelial. A DG é divididas em três tipos, o tipo I é a forma mais branda e mais prevalente da doença. As consequências desta doença incluem hepatoesplenomegalia, deficiências ósseas, manifestações hematológicas e neurodegeneração, porém os mecanismos fisiopatológicos ainda não estão totalmente esclarecidos. Portanto, a fim de esclarecer a fisiopatologia envolvida na DG, o presente estudo avaliou a produção de espécies reativas de oxigênio, as atividades da superóxido dismutase, catalase e glutationa peroxidase, os níveis de nitritos, os imunoconteúdos de iNOS e de pNF-kB, os danos ao DNA e o conteúdo sulfidrilas em diferentes componentes da sangue de indivíduos afetados. Os pacientes foram divididos em dois grupos: controles com diagnóstico negativo para DG e pacientes diagnosticados com DG tipo I, tratados com terapia de reposição enzimática. O sangue foi coletado 5 minutos antes do tratamento. Os resultados mostraram que a atividade de superóxido dismutase foi reduzida em eritrócitos, enquanto atividade da glutationa peroxidase foi aumentada no plasma de pacientes com DG. Os níveis de nitritos e o imunoconteúdo pNF-kB estavam significativamente aumentados no plasma e leucócitos, respectivamente. Ensaio do cometa foi realizada no sangue total e indicou danos no DNA. Observou-se também um dano oxidativo a proteínas, devido a redução do conteúdo sulfidrilas em plasma e eritrócitos. Nossos resultados sugerem que pacientes com DG, mesmo em tratamento, apresentam alteração no status oxidativo/nitrativo e parâmetros inflamatórios, bem como evidências de danos ao DNA no sangue, o que poderia ser, pelo menos em parte, associado à fisiopatologia da DG.
Gaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the gene encoding β-glucosidase enzyme, this enzyme deficiency leads to glucosylceramides accumulation in the lysosomes of the reticulum endothelial system. GD divided into three types, where in type I is the mildest and most prevalent form of disease. The consequences of this disease include hepatosplenomegaly, bone impairments, hematologic manifestations and neurodegeneration, but pathophysiology mechanisms are still not well elucidated. Therefore, in order to clarify the pathophysiology involved in GD, the present study evaluated reactive oxygen species production, superoxide dismutase, catalase and gluthatione peroxidase activities, nitrite levels, immunocontent of iNOS and pNF-κB, DNA damage and sulfhydryl content in differents components of blood from affected individuals.Patients were divided into two groups: controls with negative diagnosis to GD and patients diagnosed to GD type I treated with enzyme replacement therapy. Blood were collected 5 minutes before the treatment. Results showed that superoxide dismutase activity was reduced in erythrocytes…
Advisors/Committee Members: Wyse, Angela Terezinha de Souza.
Subjects/Keywords: Doença de Gaucher; Lysosomal storage disease; DNA damage; Terapia de reposição de enzimas; Estresse oxidativo; Inflammation; Dano ao DNA; Oxidative stress; Inflamação
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Turcatel, E. (2015). Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/129765
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Turcatel, Elias. “Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática.” 2015. Thesis, Universidade do Rio Grande do Sul. Accessed January 16, 2021.
http://hdl.handle.net/10183/129765.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Turcatel, Elias. “Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática.” 2015. Web. 16 Jan 2021.
Vancouver:
Turcatel E. Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2015. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10183/129765.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Turcatel E. Investigação da capacidade antioxidante, perfil inflamatório e dano ao DNA em pacientes com Doença de Gaucher tratados com a terapia de reposição enzimática. [Thesis]. Universidade do Rio Grande do Sul; 2015. Available from: http://hdl.handle.net/10183/129765
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
26.
Bruno Leite dos Anjos.
Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro.
Degree: 2010, Universidade Federal Rural do Rio de Janeiro
URL: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1570
;
http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1571
;
http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1572
► Cases of diseases induced by toxic plants in domestic herbivores are well reported throughout the world and have been studied also in Brazil. However, not…
(more)
▼ Cases of diseases induced by toxic plants in domestic herbivores are well reported throughout the world and have been studied also in Brazil. However, not much is known about the epidemiological and pathological aspectos of these conditions in free-living wildlife or bred in captivity. The risk for developing the toxicoses in captivity has been increasing, since natural habitats are destroyed by human action, and more centers of wildlife conservation and zoological comes are created. This study describes the epidemiological, biological and clinicopathological, lectin-histochemical and ultrastructural aspects of an outbreak of lysosomal storage disease of oligosaccharides induced by ingestion of Sida carpinifolia in young Sambar deer (Cervus unicolor) in the Rio-Zoo Foundation in the State of Rio de Janeiro, Brazil. Nine deer showed neurological signs characterized by motor and proprioceptive deficits. Then neurological signs were mainly depression, incoordination, dysmetria, ataxia, broad-based members, muscle tremors, loss of tongue tone, frequent falls and death. Grossly hematomas were observed secondary to trauma caused by dominant males of the flock, and whitish striations, especially in the renal cortex. Histologic changes included marked swelling/cytoplasmic vacuolization especially in neurons, progressing to neuronal lysis and axonal spheroids, in exocrine pancreas, thyroid follicular cells and renal tubular epithelial cells. In the lectin-histochemical examination the vacuoles were formed by the accumulation of oligosaccharides specially marked by the lectins WGA, WGA and Con-A. Ultrastructurally, the swelling/vacuolation corresponded to intense cytoplasmic distention of lysosomes, formation of residual bodies or dense granular fragments of membranes and mielinoides bodies. The study has shown the susceptibility of Cervus unicolor to swainsonine by ingestion of S. carpinifolia. Possibly poisoning the animals in this study was conducted by food restriction by the hierarchy among males in the group. It might also determine the marked similarity between clinical and pathological aspects in Sambar deer with the one presented by other herbivores.
Casos de doenças induzidas por plantas tóxicas em herbívoros domésticos são bastante relatados por todo o mundo e vêm sendo estudados também no Brasil. Pouco se sabe, contudo, sobre os aspectos epidemiológicos e patológicos dessas condições em animais selvagens de vida livre ou criados em cativeiro. Os riscos de desenvolvimento dessas toxicoses em cativeiros vêm aumentando, conforme os habitats naturais são destruídos pela ação humana, e mais centros de conservação de vida silvestre e zoológicos são criados. Nesse estudo são descritos os aspectos epidemiológicos, biológicos e clinicopatológicos, lectinohistoquímicos e ultraestruturais de um surto de doença do armazenamento lisossomal de oligossacarídeos induzido pela ingestão de Sida carpinifolia em cervos Sambar jovens (Cervus unicolor) no zoológico da Fundação Rio-Zoo no Estado do Rio de Janeiro. Nove cervos…
Advisors/Committee Members: Paulo Fernando de Vargas Peixoto.
Subjects/Keywords: cervus unicolor; doença do armazenamento lisossomal; glicoproteínas; neuropatologia; plantas tóxicas; Sida carpinifolia; MEDICINA VETERINARIA; swainsonina; cervus unicolor; lysosomal storage disease; glycoproteins; neuropathology; poisoning plants; Sida carpinifolia; swainsonine
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Anjos, B. L. d. (2010). Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro. (Thesis). Universidade Federal Rural do Rio de Janeiro. Retrieved from http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1570 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1571 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1572
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Anjos, Bruno Leite dos. “Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro.” 2010. Thesis, Universidade Federal Rural do Rio de Janeiro. Accessed January 16, 2021.
http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1570 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1571 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1572.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Anjos, Bruno Leite dos. “Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro.” 2010. Web. 16 Jan 2021.
Vancouver:
Anjos BLd. Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro. [Internet] [Thesis]. Universidade Federal Rural do Rio de Janeiro; 2010. [cited 2021 Jan 16].
Available from: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1570 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1571 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1572.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Anjos BLd. Doença do armazenamento lisossomal causada pela ingestão espontânea de Sida carpinifolia em cervos Sambar (Cervus unicolor) cativos no Rio de Janeiro. [Thesis]. Universidade Federal Rural do Rio de Janeiro; 2010. Available from: http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1570 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1571 ; http://bdtd.ufrrj.br//tde_busca/arquivo.php?codArquivo=1572
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul
27.
Pedroso, Pedro Miguel Ocampos.
Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul.
Degree: 2010, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/25027
► Descrevem-se os achados epidemiológicos, clínico-patológicos, ultra-estruturais e lectino-histoquímicos de herbívoros intoxicados naturalmente por Sida carpinifolia no Estado do Rio Grande do Sul, Brasil. Este estudo…
(more)
▼ Descrevem-se os achados epidemiológicos, clínico-patológicos, ultra-estruturais e lectino-histoquímicos de herbívoros intoxicados naturalmente por Sida carpinifolia no Estado do Rio Grande do Sul, Brasil. Este estudo incluiu a elaboração de três artigos. Foi realizado um estudo retrospectivo de intoxicação natural por Sida carpinifolia em bovinos no Rio Grande do Sul, outro relata pela primeira vez uma intoxicação natural por esta planta em um animal silvestre e o terceiro artigo relata os achados patológicos observados em fetos de fêmeas caprina e bovina que foram intoxicadas experimentalmente e naturalmente respectivamente por Sida carpinifolia. No primeiro artigo foram afetados cinco bovinos entre os anos de 2001 a 2008. O quadro clínico foi caracterizado por emagrecimento, incoordenação, dificuldade de locomoção, tremores generalizados, quedas frequentes e morte. Microscopicamente as principais alterações foram vacuolização dos neurônios de Purkinje do cerebelo, vacuolização das células acinares do pâncreas e das células foliculares da tireoide. No segundo artigo, o cervídeo desenvolveu uma síndrome neurológica caracterizada por fraqueza muscular, tremores de intensão, déficit visual, quedas, postura e comportamento anormal. Os principais achados microscópicos foram vacuolização citoplasmática nos neurônios de Purkinje do cerebelo. No terceiro artigo duas cabras prenhes foram intoxicadas experimentalmente com Sida carpinifolia nas doses de 10 e 13 g/kg respectivamente durante 30 dias e foram acompanhados durante 15 dias após o consumo da planta. Após este período foram eutanasiadas e necropsiadas. Adicionalmente foi incluído um feto bovino no qual a mãe havia sido intoxicada naturalmente por S. carpinifolia. As principais alterações microscópicas observadas nos fetos foram vacuolização do epitélio dos túbulos renais, das células foliculares da tireoide e cerebelo com discreta vacuolização dos neurônios de Purkinje. Na microscopia eletrônica de todos os casos foi observado vacúolos contendo material finamente granulado e delimitado por membrana. Na lectinahistoquímica dos bovinos, do cervídeo e dos fetos observou-se marcação em neurônios com as lectinas Concanavalia ensiformis (Con-A), Triticum vulgaris (WGA) e Succinyl WGA (sWGA).
Describes the epidemiological, clinical, pathological, ultrastructural and lectinhistochemical herbivore naturally poisoned by Sida carpinifolia in Rio Grande do Sul, Brazil. This study included the preparation of three articles. We conducted a retrospective study of natural poisoning by Sida carpinifolia in cattle in Rio Grande do Sul and the other reports for the first time a natural poisoning by this plant in a wild animal. The third article reports the pathologic findings observed in fetuses of female goats and cattle that were naturally and experimentally poisoned by Sida carpinifolia respectively. In the first paper were affected five cattle between the years 2001 to 2008. The clinical picture was characterized by weight loss, incoordination, difficulty walking, generalized…
Advisors/Committee Members: Driemeier, David.
Subjects/Keywords: Doença de depósito lisossomal; Sida carpinifolia; Lysosomal storage disease; Sida carpinifolia; Cattles; Patologia veterinaria; Deer; Intoxicação; Fetuses; Patologia veterinaria : Bovinos; Cervídeos silvestres; Herbívoros
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APA (6th Edition):
Pedroso, P. M. O. (2010). Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/25027
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Pedroso, Pedro Miguel Ocampos. “Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul.” 2010. Thesis, Universidade do Rio Grande do Sul. Accessed January 16, 2021.
http://hdl.handle.net/10183/25027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Pedroso, Pedro Miguel Ocampos. “Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul.” 2010. Web. 16 Jan 2021.
Vancouver:
Pedroso PMO. Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2010. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10183/25027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Pedroso PMO. Doença do armazenamento lisossomal induzida pelo consumo de Sida carpinifolia (Malvaceae) em herbívoros no Rio Grande do Sul. [Thesis]. Universidade do Rio Grande do Sul; 2010. Available from: http://hdl.handle.net/10183/25027
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Lincoln University
28.
Barry, Lucy A.
Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease.
Degree: 2011, Lincoln University
URL: http://hdl.handle.net/10182/3940
► The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited childhood diseases which result in severe cortical atrophy, blindness, seizures, and the…
(more)
▼ The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited childhood diseases which result in severe cortical atrophy, blindness, seizures, and the accumulation of fluorescent lysosome derived organelles in neurons and most other cells throughout the body. A number of naturally occurring animal models of NCL have been found, the most informative being the CLN6 form in New Zealand South Hampshire sheep. Previous studies in ovine CLN6 have shown a strong correlation between glial activation and subsequent neuronal loss, suggesting that it has a primary role in the development of disease pathology. This thesis describes changes in the expression of inflammatory mediators in affected animals, neuropathological changes that take place in chimeric animals and the implications that these findings have for future therapeutic options.
Quantitative real-time PCR revealed significant increases in the expression of pro- and anti-inflammatory cytokines, TNF-α, IL-1β, TGF-β and IL-10, in the brains of affected animals compared to normal controls. Expression of all four cytokines was significantly increased in affected animals at all ages analysed, including 6 months of age, prior to clinical disease manifestation. These results validate the central role that neuroinflammation is proposed to play in disease pathogenesis and indicates that an atypical, dysregulated inflammatory response is ongoing in affected animals.
Chimeric animals were generated by mixing homozygous affected and homozygous normal blastomeres. Genotypic and histological examination of the resulting chimeric animals indicated a good degree of colonisation of both cell types in the brain and evidence of cross-cell communication. CAT scans revealed that the brain volumes of two chimeras were within the normal brain volume range, whilst three animals had progressively recovering brain volumes. All normal and recovering-like chimeras presented with reduced or absent disease associated glial activation, no evidence of neurodegeneration, normal cortical thickness and laminar organisation of cells, and no loss of vision, long after these symptoms had progressed to terminal disease in affected animals.
PSA-NCAM staining indicated extended neurogenesis in chimeric animals. Individual
PSA-NCAM positive cells were present throughout all cortical layers in chimeric animals, in contrast to affected animals in which newly generated cells are largely confined to cellular aggregates in upper cortical layers. Genotyping brain regions of these animals indicated up to 75% of cells were genotypically affected. Despite this storage bodies were rarely observed indicating that storage had been cleared from most cells. These studies indicate that given the correct environmental milieu newly generated and affected cells can survive and are amenable to correction by normal cells in CLN6 NCL, resulting in an amelioration of disease pathology.
GFP lentiviral vectors injected into the sheep brain resulted in stable cell transductions evident up to 80 days…
Subjects/Keywords: chimeras; neurogenesis; inflammation; sheep; microglia; Batten disease; neuronal ceroid lipofuscinosis; neural stem cells; cytokines; neurodegeneration; gene therapy; lysosomal storage disorder; animal model
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Barry, L. A. (2011). Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease. (Thesis). Lincoln University. Retrieved from http://hdl.handle.net/10182/3940
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Barry, Lucy A. “Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease.” 2011. Thesis, Lincoln University. Accessed January 16, 2021.
http://hdl.handle.net/10182/3940.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Barry, Lucy A. “Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease.” 2011. Web. 16 Jan 2021.
Vancouver:
Barry LA. Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease. [Internet] [Thesis]. Lincoln University; 2011. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10182/3940.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Barry LA. Neuroinflammation and defining gene therapy approaches for ovine CLN6 Batten disease. [Thesis]. Lincoln University; 2011. Available from: http://hdl.handle.net/10182/3940
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Lincoln University
29.
Chen, Zhe (Jarol).
A molecular dissection of neuroinflammation in ovine Batten disease.
Degree: 2016, Lincoln University
URL: http://hdl.handle.net/10182/7191
► Batten disease (Neuronal ceroid lipofuscinosis, NCL) is a group of devastating neurodegenerative diseases that affect children, caused by mutations in a number of genes, but…
(more)
▼ Batten disease (Neuronal ceroid lipofuscinosis, NCL) is a group of devastating neurodegenerative diseases that affect children, caused by mutations in a number of genes, but the underlying pathogenic mechanisms remain unclear. However, the remarkable similarity of pathological features between classical forms of NCL indicates that there may be a unique pathway in which NCL proteins play a role. Immunohistochemical investigations of ovine Batten disease revealed neuroinflammation preceded neurodegeneration in a regionally specific manner. A previous study showed that chronic treatment with an anti-inflammatory compound minocycline did not inhibit the neuroinflammation, indicating the need to understand the specific neuroinflammatory cascade in Batten disease to identify likely druggable targets before embarking on drug therapies. A drug screening method is not practical in large animals. Thus, a proposed neuroinflammatory cascade was investigated in a longitudinal study of CLN6 affected sheep brains. This thesis describes the changes in selective neuroinflammatory modulators in this proposed neuroinflammatory cascade during the disease progression.
Selected neuroinflammatory modulators (TNF-α, TGF-β, IL-1β, IL-10, NF-ᴋB, MAPK14, JAK/STAT, SOCS3, MnSOD, iNOS, Trk B and BDNF) were investigated by quantitative PCR on RNA extracted from different brain regions across ages of disease development (2, 6, 9, 18 and 24 months). Longitudinal expression of MnSOD and mitochondrial marker (COX IV) was also studied by immunohistochemistry on perfusion-fixed brain sections.
The distribution of MnSOD through the cortical grey matter co-localised to mitochondria and became compressed to the boundary between layers I and II and between layers IV and V in the affected cortices at 18 and 24 months, following severe neurodegeneration. There was no such compression in the non-degenerating cerebellum and brain stem. Quantification of MnSOD and COX IV across the cortical grey matter showed that the expressions were reduced at 18 and more so at 24 months, indicating that previous reports of enhanced activity are likely to have arisen from unmatched sampling.
Anti-inflammatory SOCS3 mRNA expression was up-regulated significantly prior to neurodegeneration and concurrent to the neuroinflammation, and was accompanied by up-regulation of its protein expression. It however did not suppress the neuroinflammation. Both pro- and anti -inflammatory cytokines (TNF-α, IL-1β, TGF-β, IL-10) were upregulated at the initiation of neurodegeneration, at 4-6 months of age, prior to the onset of clinical disease and cortical atrophy evident at 10-14 months, whereas the oxidative responsive genes SOD2/MnSOD and HO-1 were not. iNOS expression was not found in sheep. NF-ᴋB, MAPK14 and JAK/STAT pathway activation followed elevation of cytokines. TrkB expression was increased in the advanced disease while BDNF expression remained unchanged. Other recently proposed neuroinflammatory modulators (PI3Ks, MT I/II/III, GRN) were also investigated. The up-regulation…
Subjects/Keywords: Batten disease; lysosomal storage disorder; neuronal ceroid lipofuscinosis; sheep; neuroinflammatory cascade; neurodegeneration; oxidative stress; Animal Model; 110904 Neurology and Neuromuscular Diseases; 060410 Neurogenetics
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chen, Z. (. (2016). A molecular dissection of neuroinflammation in ovine Batten disease. (Thesis). Lincoln University. Retrieved from http://hdl.handle.net/10182/7191
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Chen, Zhe (Jarol). “A molecular dissection of neuroinflammation in ovine Batten disease.” 2016. Thesis, Lincoln University. Accessed January 16, 2021.
http://hdl.handle.net/10182/7191.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Chen, Zhe (Jarol). “A molecular dissection of neuroinflammation in ovine Batten disease.” 2016. Web. 16 Jan 2021.
Vancouver:
Chen Z(. A molecular dissection of neuroinflammation in ovine Batten disease. [Internet] [Thesis]. Lincoln University; 2016. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10182/7191.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Chen Z(. A molecular dissection of neuroinflammation in ovine Batten disease. [Thesis]. Lincoln University; 2016. Available from: http://hdl.handle.net/10182/7191
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Lincoln University
30.
Mitchell, Nadia.
Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses.
Degree: 2016, Lincoln University
URL: http://hdl.handle.net/10182/7237
► The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited lysosomal storage diseases characterised by progressive neurodegeneration, cortical atrophy, and blindness. Currently…
(more)
▼ The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal inherited lysosomal storage diseases characterised by progressive neurodegeneration, cortical atrophy, and blindness. Currently there are no effective treatments. Naturally occurring animal models exist, including two forms in sheep which are representative of the different NCL protein defects. A lesion in a soluble lysosomal protein (CLN5) causes NCL in Borderdale sheep, whilst South Hampshire sheep have a defective intracellular endoplasmic reticulum membrane-bound protein (CLN6). This subdivision has consequences for the planning of therapies. This thesis compares the progressive neuropathological changes, and examines the efficacy of viral-mediated in vivo gene therapy, in these two NCL sheep models.
An immunohistochemical study revealed that, despite very different gene products and subcellular localisations, the pathogenic cascade was remarkably similar for CLN5 and CLN6 affected sheep. Dysregulated glial activation preceded regionally specific neurodegeneration in both disease models and both occurred well before clinical onset. Neuropathological changes were more advanced in the CLN5 model, which correlated with the earlier onset of clinical symptoms in these sheep, but by end-stage disease CLN5 and CLN6 brains were similarly affected. Windows for best therapeutic efficacy were established and these data highlight the translational utility of the sheep brain for testing human gene therapies.
Lentiviral vectors have been shown to mediate successful gene delivery to the ovine brain yet the efficacy of adeno-associated viral (AAV) vectors has not been tested in sheep. Stable, predominantly neurotropic, transgene expression was evident one month after intracerebroventricular (ICV) and intraparenchymal (IP) delivery of AAV9 to the normal sheep brain. However with a greater spread and no evidence of vector or procedural neuroinflammation or toxicity, the ICV approach proved most efficacious in sheep.
vi
Deficiencies in soluble lysosomal proteins are deemed particularly amenable to in vivo gene therapy via the normal lysosomal enzyme trafficking system and the phenomenon of ‘cross-correction’. To test this paradigm in sheep, six pre-clinical CLN5 deficient lambs were treated with combinatorial ICV and IP injections of either lentiviral or AAV9 vectors expressing ovine CLN5. Both vector platforms afforded sustained protection against stereotypical disease in these sheep. Cognitive and neurological function was preserved, whilst longitudinal neuroimaging revealed normalisation of intracranial volume and structural brain integrity. Quality of life was profoundly improved for the treated sheep and, apart from delayed-onset visual deficits, treated sheep well exceeded the typical lifespan of untreated animals.
Defects in membrane-bound proteins are generally considered harder therapeutic targets. However the current study indicates that gene therapy is also possible for these NCL forms. Whilst five similarly injected pre-clinical CLN6…
Subjects/Keywords: Batten disease; neuronal ceroid lipofuscinosis; lysosomal storage disorder; animal models; sheep; brain; neurodegeneration; neuroinflammation; neurogenesis; gene therapy; vector; adeno-associated virus; lentivirus; transduction; 1109 Neurosciences; 070709 Veterinary Pathology
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mitchell, N. (2016). Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses. (Thesis). Lincoln University. Retrieved from http://hdl.handle.net/10182/7237
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Mitchell, Nadia. “Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses.” 2016. Thesis, Lincoln University. Accessed January 16, 2021.
http://hdl.handle.net/10182/7237.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Mitchell, Nadia. “Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses.” 2016. Web. 16 Jan 2021.
Vancouver:
Mitchell N. Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses. [Internet] [Thesis]. Lincoln University; 2016. [cited 2021 Jan 16].
Available from: http://hdl.handle.net/10182/7237.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Mitchell N. Longitudinal studies and the development of gene therapy for ovine neuronal ceroid lipofuscinoses. [Thesis]. Lincoln University; 2016. Available from: http://hdl.handle.net/10182/7237
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
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