New Research In
Physical Sciences
Social Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
- Agricultural Sciences
- Anthropology
- Applied Biological Sciences
- Biochemistry
- Biophysics and Computational Biology
- Cell Biology
- Developmental Biology
- Ecology
- Environmental Sciences
- Evolution
- Genetics
- Immunology and Inflammation
- Medical Sciences
- Microbiology
- Neuroscience
- Pharmacology
- Physiology
- Plant Biology
- Population Biology
- Psychological and Cognitive Sciences
- Sustainability Science
- Systems Biology
Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa
Edited by Jeremy Nathans, The Johns Hopkins University, Baltimore, MD, and approved December 20, 2011 (received for review November 16, 2011)

Abstract
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.
Footnotes
- ↵1To whom correspondence may be addressed. E-mail: wbeltran{at}vet.upenn.edu or gda{at}vet.upenn.edu.
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.
Citation Manager Formats
Sign up for Article Alerts
Jump to section
You May Also be Interested in
More Articles of This Classification
Biological Sciences
Related Content
- No related articles found.
Cited by...
- Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector
- A Coding Variant in the Gene Bardet-Biedl Syndrome 4 (BBS4) Is Associated with a Novel Form of Canine Progressive Retinal Atrophy
- Disease mechanisms of X-linked retinitis pigmentosa due to RP2 and RPGR mutations
- RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options
- Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease
- The Status of RPE65 Gene Therapy Trials: Safety and Efficacy
- Advancing Therapeutic Strategies for Inherited Retinal Degeneration: Recommendations From the Monaciano Symposium
- Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR
- Leber Congenital Amaurosis Caused by Mutations in GUCY2D
- Ablation of the X-Linked Retinitis Pigmentosa 2 (Rp2) Gene in Mice Results in Opsin Mislocalization and Photoreceptor Degeneration
- Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid
- A spectral-domain optical coherence tomography device provides reliable corneal pachymetry measurements in canine eyes
- Reply to Townes-Anderson: RPE65 gene therapy does not alter the natural history of retinal degeneration
- The interplay between RPGR, PDE{delta} and Arl2/3 regulate the ciliary targeting of farnesylated cargo
- Seeing the Light
- What's in a Name? RPGR Mutations Redefine the Genetic and Phenotypic Landscape in Retinal Degenerative Diseases
- Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement
- Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative Disease
- RPGR-Associated Retinal Degeneration in Human X-Linked RP and a Murine Model