Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h−/− mouse
Open accessAbstract
X-linked retinoschisis, a disease characterized by splitting of the retina, is caused by mutations in the retinoschisin gene, which encodes a putative secreted cell adhesion protein. Currently, there is no effective treatment for retinoschisis, though viral vector-mediated gene replacement therapies offer promise. We used intravitreal delivery of three different AAV vectors to target delivery of the RS1 gene to Müller glia, photoreceptors or multiple cell types throughout the retina. Müller glia radially span the entire retina, are accessible from the vitreous, and remain intact throughout progression of the disease. However, photoreceptors, not glia, normally secrete retinoschisin. We compared the efficacy of rescue mediated by retinoschisin secretion from these specific subtypes of retinal cells in the Rs1h-/- mouse model of retinoschisis. Our results indicate that all three vectors deliver the RS1 gene, and that several cell types can secrete retinoschisin, leading to transport of the protein across the retina. The greatest long-term rescue was observed when photoreceptors produce retinoschisin. Similar rescue was observed with photoreceptor-specific or generalized expression, although photoreceptor secretion may contribute to rescue in the latter case. These results collectively point to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies.
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Because the retina is fragile in patients with X-linked Retinoschisis XLRS, the risk for subsequent retinal detachments increases following gene therapy if performed via the subretinal route.
“Because the retina is fragile in patients with X-linked Retinoschisis XLRS, the risk for subsequent retinal detachments increases following gene therapy if performed via the subretinal route.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [40]
The Discussion says XLRS retinas have an increased risk of detachment and that subretinal injections may pose surgical risks in these fragile retinas. It does not establish that subretinal gene therapy increases the rate of subsequent retinal detachments; the claim states that possibility as a definite outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measuredStudies performed in Rs1h knockout mice show that enduring therapy is achieved when AAV-mediated RS1 is produced within PRs.
“studies performed in Rs1h knockout mice show that enduring therapy is achieved when AAV-mediated RS1 is produced within PRs.127”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [127]
The lack of efficacy in the AAV8-RS1 XLRS trial was at least partially due to inefficient targeting of RS1 to PRs.
“Taken together, the lack of efficacy in this trial was at least partially due to inefficient targeting of RS1 to PRs.”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [127]
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- Authors
- Byrne, L. C., Öztürk, B. E., Lee, T., Fortuny, C., Visel, M., Dalkara, D., Schaffer, D. V., & Flannery, J. G.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Flannery, J G
- Venue
- Gene Therapy
- Published
- 2014-04-03
- Volume
- 21
- Issue
- 6
- Pages
- 585-592
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4047144
- OpenAlex
- W2012504059
- Cited by
- 96
- References
- 27
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 16 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 2 · 2019: 6 · 2018: 12 · 2017: 6 · 2016: 12 · 2015: 12 · 2014: 3
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (R21EY016994, PN2EY018241)
- 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
- retinoschisin, X-linked retinoschisis, adeno-associated virus vectors, intravitreal delivery, photoreceptors, Müller cells, cell adhesion proteins
- MeSH terms
- Aging, Animals, Disease Models, Animal, Electroretinography, Eye Proteins, Genetic Vectors, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Organ Culture Techniques, Retina, Genetic Therapy, Cell Adhesion Molecules, Photoreceptor Cells, Vertebrate, Retinoschisis, Green Fluorescent Proteins
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