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Development of a translatable gene augmentation therapy for CNGB1-retinitis pigmentosa.

Authors :
Occelli LM
Zobel L
Stoddard J
Wagner J
Pasmanter N
Querubin J
Renner LM
Reynaga R
Winkler PA
Sun K
Marinho LFLP
O'Riordan CR
Frederick A
Lauer A
Tsang SH
Hauswirth WW
McGill TJ
Neuringer M
Michalakis S
Petersen-Jones SM
Source :
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Jul 05; Vol. 31 (7), pp. 2028-2041. Date of Electronic Publication: 2023 Apr 13.
Publication Year :
2023

Abstract

In this study, we investigate a gene augmentation therapy candidate for the treatment of retinitis pigmentosa (RP) due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations. We use an adeno-associated virus serotype 5 with transgene under control of a novel short human rhodopsin promoter. The promoter/capsid combination drives efficient expression of a reporter gene (AAV5-RHO-eGFP) exclusively in rod photoreceptors in primate, dog, and mouse following subretinal delivery. The therapeutic vector (AAV5-RHO-CNGB1) delivered to the subretinal space of CNGB1 mutant dogs restores rod-mediated retinal function (electroretinographic responses and vision) for at least 12 months post treatment. Immunohistochemistry shows human CNGB1 is expressed in rod photoreceptors in the treated regions as well as restoration of expression and trafficking of the endogenous alpha subunit of the rod CNG channel required for normal channel formation. The treatment reverses abnormal accumulation of the second messenger, cyclic guanosine monophosphate, which occurs in rod photoreceptors of CNGB1 mutant dogs, confirming formation of a functional CNG channel. In vivo imaging shows long-term preservation of retinal structure. In conclusion, this study establishes the long-term efficacy of subretinal delivery of AAV5-RHO-CNGB1 to rescue the disease phenotype in a canine model of CNGB1-RP, confirming its suitability for future clinical development.<br />Competing Interests: Declaration of interests C.R.O. and A.F. are employees of Sanofi. S.M. is listed as inventor on the patent application WO2018172961A1 ‘‘Gene therapy for the treatment of cngb1-linked retinitis pigmentosa’’ and is co-founder of the gene therapy company ViGeneron GmbH.<br /> (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1525-0024
Volume :
31
Issue :
7
Database :
MEDLINE
Journal :
Molecular therapy : the journal of the American Society of Gene Therapy
Publication Type :
Academic Journal
Accession number :
37056049
Full Text :
https://doi.org/10.1016/j.ymthe.2023.04.005