Gene Therapy: Ophthalmology's Future?

At this year’s Association for Research in Vision and Ophthalmology meeting in Fort Lauderdale, Fla., Joan E. Bennett, M.D., Ph.D., of the University of Pennsylvania, presented startling and encouraging data from a small clinical study of a gene therapy treatment of Leber's congenital amaurosis, LCA. Roughly half of LCA cases are caused by a defect in the RPE65 gene. This gene codes for a enzyme essential for the production of rhodopsin. Lack of a functional RPE65 in the retinal pigment epithelium renders rod photoreceptor cells unable to respond to light.

Dr. Bennett’s husband, Albert M. Maguire, M.D., and an international team of colleagues also presented findings online in the New England Journal of Medicine. A parallel study by an English group was also part of this issue. The authors are quick to point out that this study is still in its earliest stages with relatively short follow-up periods. Still, media coverage of this study was wide-spread, and drew attention from all major outlets including the television networks such as ABC.

Dr. Bennett and her colleagues at at The Children's Hospital of Philadelphia (CHOP) highlighted the experience of six patients between the ages of 19 and 26 years old from the US and Italy. Three patients were treated in this first phase of the dose escalation study. Each were evaluated by: pupillometry to measure the return of pupillary light reflexes, hand motion recognition, and visual acuity by Snellen and other Near Visual Acuity charts. Though none of the patients had restoration of normal vision, the majority had modest improvement and were able to navigate obstacle courses (see NEJM video). These patients typically had vision as toddlers and some were therefore able to recognize letters after treatment. It is possible that efficacy will be improved if even younger patients were treated, ideally before amblyopia and retinal degeneration are established.

Researchers used a recombinant AAV vector made by Targeted Genetics Corp. to deliver 1.5 x 10¹⁰ copies of the RPE65 gene into the patients' retinal pigment epithelium. 150µL of “AAV2.hRPE65v2” inoculum was delivered subretinally via typical three-port pars plana vitrectomy. Though the surgeons had practiced the technique well over ten thousand times in preparation for the human studies, an asymptomatic macular hole still developed in one patient as determined by optical coherence tomography (OCT). It is unclear whether this was a surgical problem or a viral dose issue. This patient did respond well to therapy and regained some degree of retinal function.

Critics have argued that one potential hurdle to the technique is that it uses a recombinant adeno-associated virus (AAV) do deliver the healthy gene. Subjects would ideally need to be naïve to AAV, a fairly ubiquitous virus. In practice however, this issue hasn’t proven to be as significant as had been previously thought. Neutralizing antibody titers just aren’t high enough to impede gene transfer.

At the end of Dr. Bennett’s talk, an audience member at posed an interesting question. If one combined this innovation with recent published work in Science suggesting that anti-depressants such as fluoxetine could enhance neuronal plasticity in the visual system, could even better results be obtained? This study looked at interactions with brain-derived neurotrophic factor (BDNF) finding that patients may more easily overcome amblyopia. The implication is that the brains of previously blind individuals may more easily adapt to being able to see again if they were taking fluoxetine while on the gene-therapy protocol.

Gene therapy may also work for other types of eye disease. In theory, existing genes can be upregulated or downregulated depending on the therapy required. In addition to simply fixing a broken gene by replacing it with a functional copy, entirely new non-native genes can be added. For example, additional data presented at ARVO suggested that there may be a role for recombinant-AAV type 2 vectors in gene therapy for color blindness. Katherine Mancuso, MD, of the Department of Ophthalmology, Medical College of Wisconsin presented data in which gene therapy was used in a dichromatic primate model (squirrel monkeys, Saimiri sciureus) to add a third photopigment and bring about red-green vision. Twelve month data showed stability of red-green vision. The data suggest that treating adults for congenital visual conditions is possible because the brain can assimilate newly acquired visual capabilities later in life.

Consider the story of a dog named “Lancelot”, a Briard mix-breed who suffered from a canine equivalent of LCA and was treated by a similar protocol in 2000. He regained and retained the vast majority of his vision. Dozens of dogs with this form of blindness have followed in his footsteps and are now seeing well after just one treatment. If Lancelot is any indication, we just may be witnessing the beginning of a line of therapies for genetic diseases of vision. Lancelot would tell you the future is bright (pun intended).

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