TMC PULSE

t m c » p u l s e | m a r c h 2 0 1 8 6 Correcting a Gene that Causes Blindness The FDA approves gene therapy to treat patients with inherited vision loss S ixteen-year-old Amanda Martin lay on the operating table under full anesthesia, her body covered in sterile cloths one shade shy of peacock blue. Only her right eye was exposed, the word "yes" scribbled in marker above it—visual verifica- tion that it was, indeed, the correct eye. Numbing drops pooled over her cornea and spider-like surgical equipment held her lid wide open in preparation for surgery. Within minutes, Christina Y. Weng, M.D., assistant professor of ophthalmology- vitreoretinal diseases and surgery at Baylor College of Medicine's Cullen Eye Institute, would begin a pars plana vitrectomy (PPV) to remove the vitreous gel from Martin's eye. For Martin, the procedure would create space for an artificial lens, but a PPV is also part of the ground- breaking genetic therapy recently approved by the U.S. Food and Drug Administration to treat a rare form of blindness—the country's first directly administered gene therapy approved to target a disease caused by mutations in a specific gene. 'A remarkably beautiful ballet' Pharmaceutical company Spark Therapeutics got the green light in December to market Luxturna, a drug injected directly under the retina to correct a mutation on a gene called RPE65. One of the most common conditions associated with the mutation is Leber congenital amaurosis, or LCA, which is characterized by severe visual impair- ment at birth. Until now, no treatment options were available. "It's a very exciting time for the retina world right now," Weng said. "It's taken giants in the research and clinical worlds to really consolidate their efforts toward developing something that could finally treat disorders that we once thought were untreatable." The mechanics of vision are multifaceted. Light meets the cornea, travels through the pupil, the lens, and finally penetrates the gelatinous material in the center of the eye, called the vitre- ous, to reach the retina—a membrane lining the back of the eye that converts light information into electrical signals for the brain to understand. "There is a lot of complexity in how the retina does that—there are lots of moving pieces," said Timothy Stout, M.D., Ph.D., director of the Cullen Eye Institute. "Typically, these are proteins that are expressed in the retina that allow this conversion from light information to electrical information to take place. There are hundreds of thousands of moving parts that do that. It's a remarkably beautiful ballet." But as with everything in the human body, one small mutation in the genes that code these pro- tein parts can wreak havoc on the whole system. How that translates to vision impairment depends on the gene affected. "You can have some mutations that are in certain moving parts that are so absolutely delete- rious that you can't see light from day one of life," Stout said. "Then, on the other end of the spec- trum, there are problems with proteins in your retina that may be so mild that maybe when you're 70 or 80 you may have some issues, but other than that, you're good." What typically happens in Stout's clinic is that parents notice a problem—their child fails a school screening or can't see well when the lights go out or has trouble distinguishing colors. That information, he said, helps guide him toward which moving parts might be problematic, though some form of gene sequencing is required to make a conclusive diagnosis. "I might find out that the reason Johnny can't see well is because he's got a mutation in both copies of gene 'X,'" Stout said. "So what we've started to say is, 'If Johnny's not seeing because he doesn't have a normal copy of the gene 'X' and can't make protein 'X,' what if we put a normal copy of that gene into a virus and then put the virus near the cells that are affected, infect those cells with the virus, and then have that normal protein be expressed?" And that's exactly what they did for RPE65. (continued) B y A l e x a n d r a B e c k e r Christina Y. Weng, M.D., assistant professor of ophthalmology-vitreoretinal diseases and surgery at Baylor College of Medicine's Cullen Eye Institute, scrubs in for Amanda Martin's surgery. Amanda Martin waits in pre-op with her mother, Patricia Martin. Facing page: Weng performs a pars plana vitrectomy on Amanda Martin's eye to make room for an artificial lens.

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