Development of a translatable gene augmentation therapy for CNGB1-retinitis pigmentosa.
CNGB1
adeno-associated virus
dog
electroretinography
gene therapy
nonhuman primate
perifoveal chorioretinal atrophy
retinitis pigmentosa
short rhodopsin promoter
spectral domain optical coherence tomography
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 07 2023
05 07 2023
Historique:
received:
19
01
2023
revised:
07
03
2023
accepted:
10
04
2023
pmc-release:
05
07
2024
medline:
10
7
2023
pubmed:
15
4
2023
entrez:
14
4
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37056049
pii: S1525-0016(23)00203-4
doi: 10.1016/j.ymthe.2023.04.005
pmc: PMC10362398
pii:
doi:
Substances chimiques
Cyclic Nucleotide-Gated Cation Channels
0
Rhodopsin
9009-81-8
CNGB1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2028-2041Subventions
Organisme : NIH HHS
ID : P51 OD011092
Pays : United States
Organisme : NEI NIH HHS
ID : R24 EY027285
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024585
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
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