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Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk
Open accessAbstract
The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy ( rdy ) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.
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“Delivery of Ad encoding the Mertk gene to the RPE of RCS rats (a retinal degeneration model), rescued RPE dysfunction [61].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [61]
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Metadata
- Authors
- Vollrath, D., Feng, W., Duncan, J. L., Yasumura, D., D'Cruz, P. M., Chappelow, A., Matthes, M. T., Kay, M. A., & LaVail, M. M.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-10-09
- Volume
- 98
- Issue
- 22
- Pages
- 12584-12589
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC60097
- OpenAlex
- W2057314625
- Semantic Scholar
- 0d9d2bb2b8ead15d2bced09ea8f2d91745995d28
- Cited by
- 290
- References
- 45
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 12 · 2015: 14 · 2014: 11 · 2013: 13 · 2012: 15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation Fighting Blindness
- Karl Kirchgessner Foundation
- Research to Prevent Blindness (EY02162)
- Macula Vision Research Foundation
- National Institutes of Health (EY01919, EY00415)
- National Eye Institute (EY-06842, P30EY002162, EY-01919, R01EY001919, K08EY000415, F32EY006842, R01EY006842)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK049022)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- MERTK, retinal degeneration, retinal pigment epithelium, photoreceptor outer segment phagocytosis, photoreceptor degeneration, viral gene delivery, adenoviral vector, subretinal injection, complementation, retinitis pigmentosa, gene therapy, RCS rat
- MeSH terms
- c-Mer Tyrosine Kinase, Adenoviridae, Animals, HeLa Cells, Humans, Phagocytosis, Phenotype, Photoreceptor Cells, Pigment Epithelium of Eye, Proto-Oncogene Proteins, Retinal Diseases, Genetic Therapy, Receptor Protein-Tyrosine Kinases, Gene Transfer, Horizontal, Rats
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