126. Retinoschisin Gene Therapy in Photoreceptors, Muller Glia, or All Retinal Cells in the Mouse Model of X-Linked Retinoschisis
Journal: Molecular Therapy (2014)

HHS Public Access Author manuscript Author Manuscript Gene Ther. Author manuscript; available in PMC 2014 December 01. Published in final edited form as: Gene Ther. 2014 June ; 21(6): 585–592. doi:10.1038/gt.2014.31. Retinoschisin gene therapy in photoreceptors, Muller glia, or all retinal cells in the Rs1h−/− mouse Leah C. Byrne, PhD. 1,2 , Bilge E. Ozturk 1 , Trevor Lee 1 , Cecile Fortuny 1 , Meike Visel 1 , Deniz Dalkara, PhD. 1,2,3 , David V. Schaffer, PhD. 2 , and John G. Flannery, PhD. 1,† 1 Department of Molecular and Cellular Biology and The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA 94720 Author Manuscript 2 Department of Chemical and Biomolecular Engineering, Department of Bioengineering, and The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA 94720 Abstract Author Manuscript X-linked retinoschisis, a disease characterized by splitting of the retina, is caused by mutations in the retinoschisin gene, which encodes a 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 Muller glia, photoreceptors, or multiple cell types throughout the retina. Muller 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, though 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. Keywords Gene therapy; X-linked retinoschisis; AAV vectors; photoreceptors; Muller glia; cell targeting Author Manuscript Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to J.G.F. Address: University of California at Berkeley,132 Barker Hall, Berkeley, CA 94720-3190, Phone: (510) 642-0209, flannery@berkeley.edu. 3Current address: Institut de la Vision, UMRS 968 UPMC, INSERM, CNRS U7210, F-75012 Paris, France Conflict of Interest We disclose the following conflict of interest: DD, JGF, and DVS are patent holders on ShH10 for gene delivery to the retina. LB, DD, MV, JGF, and DVS are patent holders on 7m8 for delivery of gene products to retinal cells.