Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.

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State: Public
Version: Final published version
Serval ID
serval:BIB_A7D9E5D60F01
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.
Journal
Molecular therapy. Methods & clinical development
Author(s)
Cambon K., Zimmer V., Martineau S., Gaillard M.C., Jarrige M., Bugi A., Miniarikova J., Rey M., Hassig R., Dufour N., Auregan G., Hantraye P., Perrier A.L., Déglon N.
ISSN
2329-0501 (Print)
ISSN-L
2329-0501
Publication state
Published
Issued date
16/06/2017
Peer-reviewed
Oui
Volume
5
Pages
259-276
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) backbone and removing the original reporter genes. We demonstrate that this novel vector efficiently downregulated HTT expression in vitro in striatal neurons derived from induced pluripotent stem cells (iPSCs) of HD patients. It reduced two major pathological HD hallmarks while triggering a minimal inflammatory response, up to 6 weeks after injection, when administered by stereotaxic surgery in the striatum of an in vivo rodent HD model. Further assessment of this shRNA vector in vitro showed proper processing by the endogenous silencing machinery, and we analyzed gene expression changes to identify potential off-targets. These preclinical data suggest that this new shRNA vector fulfills primary biosafety and efficiency requirements for further development in the clinic as a cure for HD.

Keywords
Huntington, RNA interference, biosafety, gene expression, iPSCs, off-targets
Pubmed
Web of science
Open Access
Yes
Create date
22/06/2017 17:32
Last modification date
20/08/2019 15:12
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