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Karolinska Institute

1. Wiklander, Oscar. Therapeutic potential of extracellular vesicles .

Degree: 2017, Karolinska Institute

Extracellular vesicles (EVs) are nanometer-sized, lipid membrane enclosed, vesicles that are secreted by most, if not all, cells and contain macromolecular material of the source cell including lipids, proteins and various nucleic acid species. Over the last two decades, EVs have been recognized as important mediators of cell-to-cell communication that influence both physiological and pathological conditions. Owing to their ability to transfer bioactive components and surpass biological barriers, EVs are increasingly explored as therapeutics, both as natural delivery vectors and in its own right, as improved cell based therapies. In paper I, the great potential of EVs as therapeutic entities is explored by equipping EVs with the brain targeting rabies viral glycoprotein peptide and load them with siRNA against alpha-synuclein (a-Syn). The findings demonstrate that EVs efficiently deliver the siRNA to the target with subsequent reduction of a-Syn pathology in vitro as well as in the brains of a- Syn overexpressing transgenic mice. Thus, this indicates that targeted EVs can be employed as efficient vectors for siRNA therapy against Parkinson’s disease and other a-Syn related pathological conditions. In pursuance of using EVs for therapeutic purposes, the fate of injected EVs must be understood. Consequently, the aim of paper II was to elucidate the biodistribution of injected EVs and to investigate factors that may influence the tissue distribution of exogenous EVs. The use of the fluorescent lipophilic dye DiR was thoroughly assessed and found to be a suitable labelling method for biodistribution studies that allowed for in vivo EV tracing with high sensitivity. EVs displayed a general distribution pattern with high accumulation in liver, lung and spleen, which is in line with previous findings of mononuclear phagocyte system (MPS)-associated EV uptake. In addition, the biodistribution profile of EVs was, to a varying degree, influenced by the administration route, cell source, dosing and targeting. These variables may thus be adopted for future EV-based therapies to reflect the preferred biodistribution and/or pharmacokinetic profile for a given therapeutic approach. Furthermore, EVs have been found to convey the beneficial immunomodulatory effects of mesenchymal stromal cell (MSC)-based cell therapy. Based on these findings and studies demonstrating that EVs can be engineered to display surface moieties, the objective of paper III was to produce MSC-derived EVs that express therapeutic proteins. A chimeric construct, with an EV sorting domain fused to a non-signalling cytokine receptor, was introduced to the parental cell to produce EVs that can sequester cytokines, termed decoy EVs. By targeting the central inflammatory pathways of TNFa and IL-6 trans-signalling, these decoy EVs significantly ameliorate systemic inflammation and neuroinflammation in vivo. This novel concept thus combines the beneficial effects of stem cell therapy, EVs as delivery agents and …

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Wiklander, O. (2017). Therapeutic potential of extracellular vesicles . (Thesis). Karolinska Institute. Retrieved from http://hdl.handle.net/10616/46117

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):

Wiklander, Oscar. “Therapeutic potential of extracellular vesicles .” 2017. Thesis, Karolinska Institute. Accessed June 18, 2018. http://hdl.handle.net/10616/46117.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Wiklander, Oscar. “Therapeutic potential of extracellular vesicles .” 2017. Web. 18 Jun 2018.

Vancouver:

Wiklander O. Therapeutic potential of extracellular vesicles . [Internet] [Thesis]. Karolinska Institute; 2017. [cited 2018 Jun 18]. Available from: http://hdl.handle.net/10616/46117.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wiklander O. Therapeutic potential of extracellular vesicles . [Thesis]. Karolinska Institute; 2017. Available from: http://hdl.handle.net/10616/46117

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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