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Gene therapy new frontier for ocular disorders


The advent of gene therapy poses a new area of drug development for inherited and acquires ocular disorders.


Take-home message: The advent of gene therapy poses a new area of drug development for inherited and acquires ocular disorders.



By Fred Gebhart; Reviewed by Szilárd Kiss, MD

New York-Ophthalmologists are about to get a new tool to treat a broad range of inherited and acquired ocular disorders.

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Gene therapy could be approved as early as 2016 or 2017 to treat inherited disorders such as Leber’s congenital amaurosis (LCA) and retinitis pigmentosa (RP). Gene therapies for acquired disorders, such as diabetic retinitis and neovascular age-related macular degeneration, could follow in short order.

“Gene therapy is already a reality,” said Szilárd Kiss, MD, director of clinical research and associate professor of ophthalmology, Weill Cornell Medical College, New York. “The first gene therapy was approved in the European Union (EU) in 2013. The eye is a unique space, small and confined with well-defined genetic disorders that can be treated with a single protein delivered using a non-replicating viral vector.”

Dr. Kiss explored the coming upheaval in ocular disease treatment. Human gene therapy trials have been carried out at more than a dozen different sites involving more than 270 eyes. Researchers have reported no serious adverse events associated with the viral vectors and some significant success in treating inherited conditions such as LCA and RP.

The concept behind gene therapy is straightforward: deliver a gene that is designed to produce a therapeutic protein. In the case of Glybera, the gene therapy approved by the EU, a viral vector delivers a gene that produces a protein to treat lipoprotein lipase deficiency. In the case of LCA, a genetically modified adeno-associated virus (AAV) delivers a gene that produces a missing protein responsible for the disease.

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One form of LCA is caused by a mutation to the RPE65 gene, resulting in childhood blindness. RPE65 is expressed in the retinal pigment epithelium, which plays a role in the development and maintenance of photoreceptors. The gene also encodes a protein that helps to convert light striking the retina into electrical signals transmitted by the optic nerve. Lack of the protein disrupts the visual cycle, resulting in progressive visual impairment and ultimately to blindness.

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There are currently no treatments for LCA, Dr. Kiss noted, but several companies are developing gene therapies to deliver a functional RPE65 gene to restore vision. At least one pivotal phase III trial using gene therapy to treat LCA will likely be submitted to the FDA for approval later this year.

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All of the key ingredients needed for successful ocular gene therapy are in place, Dr. Kiss noted. Researchers have developed a menu of successful vectors that target different layers of the retina to deliver genes to treat different diseases. They have identified target genes responsible for specific diseases, have created successful animal models, surgical approaches, outcomes measures and safety data.

AAVs that target the nerve fiber layer may be useful for the treatment of glaucoma while vectors that target the Muller cells could treat X-linked retinoschesis. Vectors that transfect photoreceptors may be useful for some forms of RP while other vectors that transfect the RPE and choroid are more appropriate for other forms of retinal degeneration as well as wet and dry AMD.

Current approaches deliver therapeutic vectors via intravitreal or subretinal injection. The vector is a protein envelope, or capsid, with its native DNA replaced by the target gene and a promoter. The promoter enhances the activity of the gene to boost production of the target protein. To treat a genetic disorder such as LCA, the target gene produces the missing protein responsible for disease, RPE65 in this case. To treat acquired disorders such as neovascular age-related macular degeneration, the target gene produces a therapeutic protein such as an anti-VEGF molecule sFLT.

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Both the intravitreal and subretinal approaches can offer efficient transduction and long-term expression of the target protein. Vectors are non-pathogenic, have low immunogenicity, are non-replicating and do not integrate with the ocular genome. 

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Both routes have advantages and disadvantages. Intravitreal injection is 100 to 1,000-fold less efficient than subretinal injection. But the subretinal route is more invasive and may not be acceptable in some disorders due to compromised retinal structure.

“Gene therapy may be the only way to treat inherited diseases like LCA, RP, Stargardt’s, choroideremia, X-linked retinoschisis, achromatopisa and red-green color vision deficiency,” Dr. Kiss said. “But if you think about the impact on vision overall, there are many more people with acquired conditions like age-related macular degeneration, diabetic retinopathy or glaucoma. That is where gene therapy may ultimately have its broadest impact.”

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Ophthalmologists will not see immediate changes in treatment for the acquired diseases that account for the bulk of ophthalmologic practice, he continued. But clinicians who have patients with inherited ocular disorders should already be adjusting their practice.

“If you have a patient with one of these inherited disorders, the time is now to make sure they are referred to a center where they can enroll in the ongoing clinical trials or be ready for gene therapy as it is approved,” he said. “Gene therapy is about to change the way we treat ocular disease.”


Szilárd Kiss, MD

E: szk7001@med.cornell.edu

This article was adapted from Dr. Kiss’ presentation at the 2015 meeting of the American Society of Retinal Specialists. Dr. Kiss discloses a proprietary interest in Avalanche and Genzyme.

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