Retinal physicians are very familiar with the benefits of local delivery of drugs and therapeutic proteins to the eye. Intravitreous injection of VEGF-neutralizing proteins has revolutionized the treatment of retinal and choroidal vascular diseases, and the same characteristics of the eye that make it possible to deliver therapeutic levels of those proteins to the retina, with low exposure to other organs of the body where they are harmful, are also advantages for gene therapy. This has fueled progress in ocular gene therapy. Over the next decade, ocular gene therapy will become widely used.

This special edition of Retinal Physician, supported by REGENXBIO, is meant to review some of the progress and explain how ocular gene therapy is likely to be incorporated into the management of retinal diseases in the near future. “Retina Conversations: A Historical Perspective on Gene Therapy” provides some background and perspective. A major application for ocular gene therapy is gene augmentation to treat inherited retinal degenerations, in which there is loss of a protein critical for function and survival of a retinal cell. This is highlighted by the recent approval of voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) for Leber congenital amaurosis due to a mutation in RPE65. Dominant mutations result in production of a toxic protein, which is more complicated because knockdown of the toxic gene product must be combined with augmentation of the normal gene product. Another approach is gene editing to correct the mutation. Progress in this area is presented in “Gene Therapy for Inherited and Rare Retinal Disease.” Ocular gene therapy is also used to provide sustained expression of therapeutic proteins summarized in “The Eye as a Biofactory.”

The most advanced application of this sustained delivery approach is gene transfer for expression of a VEGF-neutralizing protein for treatment of retinal and choroidal vascular diseases. The first clinical trials in this area focusing on neovascular AMD are reviewed in “Gene Therapy for Neovascular AMD.”

There is no need for anti-VEGF proteins to enter cells because by binding VEGF in the extracellular compartment they limit its interaction with ocular blood vessels and hence reduce vascular leakage and neovascularization. In contrast, DNA and RNA must enter cells to exert their effect, which requires a carrier or vector. Viruses are adept at entering cells because they have protein coats called capsids that bind proteins on the surface of cells that help them enter. Removal of viral genes and insertion of a therapeutic transgene allows the capsid to deliver the transgene into cells that have the appropriate binding protein on their surface. Adeno-associated viral (AAV) vectors are the most widely used vectors for ocular gene therapy. There are several different serotypes of wild type AAV vectors that have different tropisms and new AAV vectors engineered/selected for characteristics advantageous for ocular gene therapy. This is reviewed in “Vector Considerations for Ocular Gene Therapy.”

Subretinal injection of AAV vectors results in strong transduction of photoreceptors and RPE in the region of the bleb (detachment) created by the injection; the technique is described in “Surgical Techniques for Delivery of Gene Therapy.” The potential advantages of a new, less invasive approach is described in “Suprachoroidal Gene Transfer.”

The collection of articles in this issue of Retinal Physician will help update retina specialists on the rapidly advancing field of ocular gene therapy. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by REGENXBIO.