Gene therapy preserved vision in a study involving dogs with naturally occurring, late-stage retinitis pigmentosa, according to research funded by the National Eye Institute (NEI), part of the NIH. The findings should contribute to the groundwork needed to move gene therapy forward into clinical trials for people with the blinding eye disorder, for which there is currently no cure.

Scientists from the University of Pennsylvania and the University of Florida, Gainesville also determined for the first time that gene therapy may be of potential benefit even after there has been significant loss of cells in the eye. Up to this point, animal studies had shown benefits from gene therapy only when it was used in the earliest stages of the disease.

“The study shows that a corrective gene can stop the loss of photoreceptors in the retina, and provides good proof of concept for gene therapy at the intermediate stage of the disease, thus widening the therapeutic window,” said Neeraj Agarwal, Ph.D., a program director at NEI.

Retinitis pigmentosa is the most common inherited disease that causes degeneration of the retina, the light-sensitive tissue lining the back of the eye. About 70% of people with the X-linked form carry mutations that cause loss of function of the retinitis pigmentosa GTPase Regulator (RPGR) gene, which encodes a protein important for maintaining the health of photoreceptors. The disease damages both rods and cones.

To overcome the effects of RPGR mutations, the researchers packaged healthy RPGR genes into an adeno-associated virus that is not known to cause any human diseases. The aim is for the virus to deliver the genes into retinal cells and for the genes to produce the RPGR protein.


NEI-funded researchers, led by the University of Pennsylvania, tested the impact of gene
therapy on a dog's vision by comparing how well it navigated an obstacle course using its
untreated eye, and then its treated eye. [Drs. William A. Beltran and Artur V. Cideciyan
of the University of Pennsylvania]


The researchers then tested the gene therapy in a naturally occurring canine form of RPGR X-linked retinitis pigmentosa that appears among some mixed breeds. Dogs with early to late stages of the disease were treated with the therapy in one eye; the untreated eye was evaluated as the control. Their results of the study (“Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease”) are published in Proceedings of the National Academy of Sciences.

Serial imaging suggested that the therapy halted the thinning of the retinal layer where photoreceptors are located and that commonly degenerates from the disease. Using immunolabeling, a technique that helps tag features inside cells, the researchers showed that the structure of rod and cone photoreceptors was improved in the treated eye and better preserved when compared to the untreated eye.

Electrical recordings from the retina also suggested that the therapy preserved cell function. Overall, the findings suggest that gene therapy halted disease-associated cell death for at least the length of the 2.5-year study.

Even in dogs with later-stage disease, gene therapy halted the loss of retinal thickness and preserved the structure of surviving photoreceptors. By contrast, untreated eyes continued to lose retinal thickness and photoreceptor function. Visual performance under dim light in an obstacle course, and in a maze that required detecting a dim light, were also significantly better in dogs using their treated eye compared with the untreated eye.

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