A team led by the School of Veterinary Medicine and the Scheie Eye Institute at the Perelman School of Medicine has shown that they can cure the canine form of X-linked retinitis pigmentosa (XLRP), a severe blinding disease, over the long term, even when the gene therapy treatment is given after half or more of the affected photoreceptor cells have been destroyed.
The work builds on earlier research that began treatment very early in the disease course, in a preventive mode or immediately after photoreceptor cells began dying.
“Now we’ve gone further, showing that the treatment is long-lasting and effective even when started at mid- and late-stage disease,” says William A. Beltran, co-lead author of the study and an associate professor of ophthalmology at Penn Vet.
“Because the progression of disease in dogs matches up with the progression in humans, this gives us a lot of confidence about translating these results to eventually treat humans,” says Artur V. Cideciyan, co-lead author and research professor of ophthalmology at Penn Medicine.
Penn Vet’s Gustavo Aguirre, the paper’s senior author and a professor of medical genetics and ophthalmology, and Penn Medicine’s Samuel Jacobson, a professor of ophthalmology, also closely collaborated on the work, which appears this week in Proceedings of the National Academy of Sciences.
XLRP arises primarily from mutations in the RPGR gene, leading to progressive vision loss starting at a young age.
The Penn team used a gene therapy approach to deliver a normal copy of RPGR to rod and cone cells. While they had already reported success when dogs with XLRP were given treatment at 5 weeks of age, the new study began the gene therapy intervention at two later time points: at 12 weeks of age, which the researchers term “mid-stage disease,” when approximately 40 percent of the eye’s photoreceptor cells have already died, or at 26 weeks of age, “late-stage disease,” when about 50 to 60 percent of the rods and cones were lost.
The researchers were pleased to find that the dogs’ vision deterioration appeared to come to a stop in the region of the retina where the gene therapy was given, and there were some signs that the structural abnormalities in the rods and cones were reversed. Perhaps most promising, the dogs showed that the treatment improved their performance on tests of visual behavior, even up to two-and-a-half years after treatment in the late-stage group.
The group hopes to employ similar strategies to develop interventions that would treat other forms of blindness caused by genes related to RPGR.