Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h−/− mouse

• Published in: Gene therapy Vol. 21; no. 6; pp. 585 - 592
• Main Authors: Byrne, L C, Öztürk, B E, Lee, T, Fortuny, C, Visel, M, Dalkara, D, Schaffer, D V, Flannery, J G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2014; Nature Publishing Group
• Subjects: 631/61/51/201; 692/699/3161/3175; Aging; Animal experimentation; Animals; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell adhesion; Cell Adhesion Molecules - genetics; Cell Biology; Disease Models, Animal; Electroretinography; Eye diseases; Eye Proteins - genetics; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy - methods; Genetic Vectors - genetics; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; Human Genetics; Humans; Mice, Inbred C57BL; Mice, Mutant Strains; Mueller cells; Nanotechnology; Organ Culture Techniques; original-article; Photoreceptor Cells, Vertebrate - physiology; Photoreceptors; Physiological aspects; Protein transport; Retina; Retina - cytology; Retina - physiology; Retinal degeneration; Retinoschisis; Retinoschisis - genetics; Retinoschisis - therapy; Rodents; Secretion
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2014.31

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.