Editors' ChoiceRetinitis Pigmentosa

Eye-Opening Experience

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Science Translational Medicine  08 Feb 2012:
Vol. 4, Issue 120, pp. 120ec22
DOI: 10.1126/scitranslmed.3003794

I can see clearly now the rain is gone,

I can see all obstacles in my way

Gone are the dark clouds that had me blind

It’s gonna be a bright … sunshiny day.

—Johnny Nash

Johnny Nash’s popular refrain epitomizes new work by Beltran and colleagues that uses gene therapy to treat one form of retinitis pigmentosa, a group of progressive genetic eye conditions that leads to incurable blindness. In particular, the X-linked form of the disease is caused by mutations in the gene that encodes the retinitis pigmentosa guanosine triphosphatase (GTPase) regulator (RPGR), a ciliary protein in photoreceptor cells of the eye. Currently, there is no effective treatment for this condition.

The authors used two dog models, each with a different relevant deletion in RPGR. These deletions specify two distinct disease phenotypes that correspond to the spectrum of human X-linked retinitis pigmentosa (XLRP): X-linked progressive retinal atrophy 1 (XLPRA1) is a progressive juvenile-onset condition, and XLPRA2 has an earlier onset and is rapidly progressive, both leading to blindness. The researchers characterized the disease characteristics of the canine model using noninvasive procedures. Specifically, by mapping the topography of the outer nuclear layer (ONL) of photoreceptor cells across the retina of the dogs and patients with XLRP and by measuring rod and cone retinal function with electroretinographic testing (ERG), the authors showed sufficient overlap between the disease phenotypes in dogs and humans to validate the use of the dog models to predict outcome in human patients.

After verifying the model, Beltran performed subretinal injections of an adeno-associated virus vector that contained the wild-type human RPGR gene, whose expression was driven by either the human IRBP (interphotoreceptor retinoid-binding protein) or the GRK1 (G-protein–coupled receptor kinase) promoter into both XLPRA1 and XLPRA2 canines. Retinal mapping revealed that photoreceptor cells were preserved through preservation of ONL in the treated dogs ascompared with the control group, which were given a balanced salt solution. Topographical mapping was confirmed with histology and immunofluorescence and showed increased photoreceptor density on the photoreceptor cells. In addition, ERG signals were larger in the treated dogs as compared to controls. These data show that the gene therapy treatment effectively preserved photoreceptor structure and function in the treated dogs. Importantly, secondary benefits were achieved through preservation of the outer plexiform layer, where the photoreceptors are located, and inner retinal abnormalities were prevented or reversed in treated dogs.

This proof-of-concept preclinical study in a large animal model provides data that encourages further development of an adeno-associated virus–mediated treatment strategy for XLRP. The authors will need to repeat the study in a much larger sample size in order to draw definitive conclusions. However, with these exciting results patients and researchers can begin to at least hum, “I can see clearly now….”

W. A. Beltran et al., Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc. Natl. Acad. Sci. U.S.A. 23 January 2012 (10.1073/pnas.1118847109). [Abstract]

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