A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.

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Serval ID
serval:BIB_BF66B3F58A82
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.
Journal
British Journal of Clinical Pharmacology
Author(s)
Chtarto A., Bockstael O., Tshibangu T., Dewitte O., Levivier M., Tenenbaum L.
ISSN
1365-2125 (Electronic)
ISSN-L
0306-5251
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
76
Number
2
Pages
217-232
Language
english
Notes
Publication types: Journal Article Publication Status: ppublish
Abstract
Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.
Pubmed
Web of science
Open Access
Yes
Create date
22/08/2013 16:22
Last modification date
20/08/2019 15:33
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