Proceedings of the National Academy of Sciences (PNAS) 2012 ; published ahead of print January 23, 2012, doi:10.1073/pnas.1118847109
Gene defects in dogs and people cause a progressive, inherited blindness called Retinitis Pigmentosa (XLRP). Gene therapy treatment developed at the University of Pennsylvania was able to treat this disease in dogs.
“While the exact disease mechanism of the RPGR form of XLRP is still unknown, the researchers were able to successfully treat dogs with two different RPGR mutations. The mutations disrupt photoreceptors in different ways, but both ultimately cause them to become useless for vision. While this form of blindness is rare in dogs, it is common in humans. Patients with XLRP usually begin to lose night vision as children and become almost totally blind by middle age. “
This is the first proof that this condition is treatable in an animal model; a single subretinal injection administered to the diseased dogs led to functional and structural recovery. The disease is much more common in people than in dogs.Treatment was able to repair the diseased part of the eye.
Researchers hope that in a few years this may be a viable treatment to prevent patients from losing their site due to this disease.
Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa
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.