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

Autor:	Occelli LM; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., Zobel L; Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Department of Ophthalmology, University Hospital, LMU Munich, 80336 Munich, Germany., Stoddard J; Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185(th) Avenue, Beaverton, OR 97005, USA., Wagner J; Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany., Pasmanter N; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., Querubin J; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., Renner LM; Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185(th) Avenue, Beaverton, OR 97005, USA., Reynaga R; Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185(th) Avenue, Beaverton, OR 97005, USA., Winkler PA; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., Sun K; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., Marinho LFLP; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA., O'Riordan CR; Genomic Medicine Unit, Sanofi, 225 Second Avenue, Waltham, MA 02451, USA., Frederick A; Genomic Medicine Unit, Sanofi, 225 Second Avenue, Waltham, MA 02451, USA., Lauer A; Casey Eye Institute, Oregon Health & Science University, 515 Campus Drive, Portland, OR 97239, USA., Tsang SH; Jonas Children's Vision Care, Departments of Ophthalmology, Pathology and Cell Biology, Institute of Human Nutrition, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Hauswirth WW; Department of Ophthalmology, College of Medicine, University of Florida, Box 100284 HSC, Gainesville, FL 32610, USA., McGill TJ; Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185(th) Avenue, Beaverton, OR 97005, USA; Casey Eye Institute, Oregon Health & Science University, 515 Campus Drive, Portland, OR 97239, USA., Neuringer M; Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185(th) Avenue, Beaverton, OR 97005, USA; Casey Eye Institute, Oregon Health & Science University, 515 Campus Drive, Portland, OR 97239, USA., Michalakis S; Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Department of Ophthalmology, University Hospital, LMU Munich, 80336 Munich, Germany. Electronic address: michalakis@lmu.de., Petersen-Jones SM; College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA. Electronic address: peter315@msu.edu.
Jazyk:	angličtina
Zdroj:	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.
DOI:	10.1016/j.ymthe.2023.04.005
Abstrakt:	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. 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. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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