Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2017 Jun 13

PMID 28603746

Citations 10

Authors

Karine Cambon

Virginie Zimmer

Sylvain Martineau

Marie-Claude Gaillard

Margot Jarrige

Aurore Bugi

Jana Miniarikova

Maria Rey

Raymonde Hassig

Noelle Dufour

Gwenaelle Auregan

Philippe Hantraye

Anselme L Perrier

Nicole Deglon

Affiliations

Soon will be listed here.

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 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.

Citing Articles

[Disease-modifying treatment approaches in Huntington disease : Past and future].

Frank W, Lindenberg K, Muhlback A, Lewerenz J, Landwehrmeyer G Nervenarzt. 2021; 93(2):179-190.

PMID: 34762178 PMC: 8825394. DOI: 10.1007/s00115-021-01224-8.

Recent advances in lentiviral vectors for gene therapy.

Wang X, Ma C, Labrada R, Qin Z, Xu T, He Z Sci China Life Sci. 2021; 64(11):1842-1857.

PMID: 34708326 DOI: 10.1007/s11427-021-1952-5.

LncRNA-H19 gene plays a significant role in regulating glioma cell function.

Liu P, Huang X, Wu H, Yin G, Shen L Mol Genet Genomic Med. 2021; 9(10):e1480.

PMID: 34477331 PMC: 8580082. DOI: 10.1002/mgg3.1480.

Maximizing lentiviral vector gene transfer in the CNS.

Humbel M, Ramosaj M, Zimmer V, Regio S, Aeby L, Moser S Gene Ther. 2020; 28(1-2):75-88.

PMID: 32632267 PMC: 7902268. DOI: 10.1038/s41434-020-0172-6.

[Gene-selective treatment approaches for Huntington's disease].

Muhlback A, Lindenberg K, Saft C, Priller J, Landwehrmeyer G Nervenarzt. 2020; 91(4):303-311.

PMID: 32179957 DOI: 10.1007/s00115-020-00882-4.

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