Gene Therapy Restores Vision but Fails to Save Rods, Cones

A gene therapy that significantly improves vision in a form of Leber congenital amaurosis (LCA) does not slow global degeneration of photoreceptors, according to a report published online January 22 in the Proceedings of the National Academy of Sciences.

Several clinical trials have demonstrated the safety of gene transfer for LCA type 2, also known as RPE65-LCA. Patients received a single subretinal injection, above the fovea, of adeno-associated virus bearing functional copies of the RPE65 gene. One eye was treated months or years before the second eye.

Vision improved quickly and enduringly in most of the clinical trial participants. "The paper proves the value of gene therapy — we can improve vision for at least several years. Saving the photoreceptors long-term is just not as easy as we had originally hoped," Gerald Chader, PhD, chief scientific officer at the Doheny Retina Institute, Los Angeles, California, told Medscape Medical News. Dr. Chader was not involved in the current study.

LCA2 is 1 of 18 genetic types of the disorder and results from autosomal recessive mutations in the RPE65 gene, which encodes an all-trans-retinyl ester isomerase essential to generate 11-cis-retinal, the form of vitamin A that photoreceptors use. The protein functions in the retinal pigment epithelium, which supports the photoreceptors.

A natural model of LCA2, the dog, provided compelling preclinical evidence that gene transfer could improve vision.

In the current study, Artur V. Cideciyan, PhD, from the Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, and colleagues evaluated visual function and photoreceptor degeneration in treated and untreated eyes of RPE65-LCA patients and dogs. They used optical coherence tomography to take serial measurements of the thickness of the outer photoreceptor nuclear layer. Thinning indicates degeneration of the rods and cones.

The researchers conducted serial exams over the course of 1.2 to 6.7 years to track the natural history of photoreceptor degeneration in 15 patients, aged 7 to 29 years at the first visit. They found that degeneration was variable and widespread.

Outer photoreceptor nuclear layer thickness was compared in 3 ways: retinal regions in the same eye over time, corresponding retinal regions in the treated and untreated eyes of the same individual, and retinal regions of treated eyes compared with natural history data on degeneration from untreated patients.

Although visual sensitivity improved dramatically in the treated eyes, photoreceptor degeneration mirrored the natural history of the untreated eyes. "[A]ll three analysis methods supported the conclusion that gene therapy has not modified the natural history of progressive retinal degeneration in the RPE65-LCA patients," the researchers conclude.

Team members from the School of Veterinary Medicine at the University of Pennsylvania in Philadelphia provided longitudinal data from the eyes of dogs that suggest an explanation for the continued photoreceptor degeneration in the human eye after gene therapy: In the dogs, gene therapy performed before the photoreceptors began to degenerate seemingly saved them, but gene therapy administered after degeneration had already started did not prevent further loss of photoreceptors.

The difference between the canine and human response reflects differences in development. At least a quarter of a dog's lifetime (equivalent to 30 human years) passes before photoreceptors begin to degenerate. In humans with RPE65-LCA, retinal degeneration is present from very early childhood. Therefore, preclinical experiments might have been more meaningful if older dogs had been treated.

Weng Tao, MD, PhD, chief scientific officer at Neurotech USA, suggested another hypothesis to Medscape Medical News to explain the observations: "Gene replacement in this case restored function but did not remove the defective gene, which probably was responsible for the continued degeneration of the photoreceptors." The transgene remains extrachromosomal in the LCA2 gene therapy.

The investigators write that the clinical trials moved too quickly to adequately assess natural history and call for reexamination of gene therapy delivery.

Coupling gene therapy with other treatments to slow retinal degeneration may be optimal, according to the researchers and several commentators. "Neurotrophic factors, antiapoptotic agents, and antioxidants will probably help. But there are significant hurdles to overcome in doing this, not least of which would be securing [US Food and Drug Administration] approval for a dual approach and the time factor in repeating studies," Dr. Chader said.

Steven Gray, PhD, a researcher at the gene therapy center at the University of North Carolina at Chapel Hill, emphasizes that the vision improvements are extraordinary. "We knew from the clinical trials that only a small portion of the retina received the gene therapy, and that still left the rest of the retina damaged and deteriorating, which could have spill-over toxicity to the treated area. It said a lot about the plasticity of the visual system and its ability to rewire itself to rely on the 'fixed' area of the retina. The Leber's trials are very encouraging, but this paper highlights the need to keep trying to make the gene delivery technology better," he told Medscape Medical News.

Dr. Hauswirth owns equity in AGTC Inc, which is commercializing use of AAV in RPE65-LCA gene therapy. Dr. Lewis is the author of The Forever Fix: Gene Therapy and the Boy Who Saved It (St. Martin's Press, 2013). The commentators have disclosed no relevant financial relationships.

Proc Natl Acad Sci USA. Published online January 22, 2013. Abstract