Edited by Jeremy Nathans, The Johns Hopkins University, Baltimore, MD, and approved December 20, 2011 (received for review November 16, 2011)
Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5–vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.
Author contributions: W.A.B., A.V.C., S.G.J., and G.D.A. designed research; W.A.B., A.V.C., A.S.L., S.I., A. Sumaroka, A.J.R., M.S., T.S.A., S.G., A. Swaroop, W.W.H., S.G.J., and G.D.A. performed research; A.S.L., H.K., A. Sumaroka, V.A.C., D.S.F., W.-T.D., S.L.B., A. Swaroop, and W.W.H. contributed new reagents/analytic tools; W.A.B., A.V.C., A. Sumaroka, A.J.R., M.S., S.G.J., and G.D.A. analyzed data; and W.A.B., A.V.C., S.G.J., and G.D.A. wrote the paper.
Conflict of interest statement: The authors declare a conflict of interest. W.W.H. and the University of Florida have a financial interest in the use of adeno-associated virus therapies and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work. The remaining authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1118847109/-/DCSupplemental.
