Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector
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Significance A number of gene-augmentation strategies are entering clinical trials for the treatment of inherited retinal blindness. Gene therapy for autosomal dominant diseases faces significant obstacles that include allelic heterogeneity and the potential need to silence the mutated gene. Here we show that a single-gene therapy vector that combines knockdown of the causative gene with its replacement by a resistant wild-type copy can prevent photoreceptor cell death and vision loss in a canine model of autosomal dominant retinitis pigmentosa.
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In a canine model of RHO-associated retinitis pigmentosa, this vector preserved retinal structure and function for up to 8 months.
“This gene therapy vector has been tested in a canine model of RHO-associated retinitis pigmentosa, which showed preservation of retinal structure and function up to 8-months follow-up.”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Cideciyan 2018
Cideciyan et al. built an AAV vector that delivers an shRNA to silence endogenous RHO while providing a codon-modified wild-type RHO that resists RNA interference.
“Cideciyan et al. constructed an AAV vectors which delivers a short hairpin RNA (shRNA) that silences endogenous RHO gene expression while introducing a codon-modified version of wild-type RHO that is resistant to the RNA interference [Cideciyan 2018].”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Cideciyan 2018
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Self-citationChan, Y. K., Dick, A. D., Hall, S. M., Langmann, T., Scribner, C. L., Mansfield, B. C., & for the Ocular Gene Therapy Inflammation Working Group (2021) · Translational Vision Science & Technology · doi:10.1167/tvst.10.4.3 · Cited by 56 · see citing works
Engineered Capsids for Efficient Gene Delivery to the Retina and Cornea
Frederick, A., Sullivan, J., Liu, L., Adamowicz, M., Lukason, M., Raymer, J., Luo, Z., Jin, X., Rao, K. N., & O'Riordan, C. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.070 · Cited by 35 · see citing works
Gene Therapy for Inherited Retinal Degeneration
Arbabi, A., Liu, A., & Ameri, H. (2019) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2018.0087 · Cited by 30 · see citing works
Kovacs, K. D., Ciulla, T. A., & Kiss, S. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2121646 · Cited by 20 · see citing works
Correcting visual loss by genetics and prosthetics
Xue, K., & MacLaren, R. E. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2020.03.003 · Cited by 5 · see citing works
- Authors
- Cideciyan, A. V., Sudharsan, R., Dufour, V. L., Massengill, M. T., Iwabe, S., Swider, M., Lisi, B., Sumaroka, A., Marinho, L. F., Appelbaum, T., Rossmiller, B., Hauswirth, W. W., Jacobson, S. G., Lewin, A. S., Aguirre, G. D., & Beltran, W. A.
- Affiliations
- University of Pennsylvania (US)
- University of Florida (US)
- Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
- University of Florida Health (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-08-20
- Volume
- 115
- Issue
- 36
- Pages
- E8547-E8556
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6130384
- OpenAlex
- W2888444358
- Cited by
- 147
- References
- 86
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 11 · 2023: 17 · 2022: 19 · 2021: 28 · 2020: 28 · 2019: 20 · 2018: 1
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Eye Institute (R24-EY022012, R01-EY06855, P30-EY001583, P30-EY021721)
- Foundation Fighting Blindness (C-GT-0414-0634-UPA01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- rhodopsin, gene therapy, autosomal dominant retinitis pigmentosa, adeno-associated virus vectors, gene knockdown, gene replacement, photoreceptor cell death, allelic heterogeneity, canine model, vision loss
- MeSH terms
- Dependovirus, Animals, Dogs, Genetic Vectors, Humans, Retinitis Pigmentosa, Rhodopsin, Genetic Therapy, RNA, Catalytic, Retinal Rod Photoreceptor Cells, Gene Knockdown Techniques, Gene Knock-In Techniques, HEK293 Cells
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