TMC PULSE

t m c » p u l s e | m a r c h 2 0 1 8 8 Fourth-grade graduation Leber congenital amaurosis is so rare it is thought to affect only a few thousand individuals in the U.S. But it presented a perfect opportunity for gene therapy trials because it is caused by a relatively straightforward mutation. The disease typically manifests when both parents carry and pass on a copy of the mutation, an inheritance pattern known as autosomal recessive. "What we've done is we've put a normal copy of the human RPE65 gene into an adeno- associated virus, which infects the right cells inside the eye but doesn't cause disease," explained Stout, who worked on the research trials that led to the development of Luxturna. "Viruses have evolved over millions of years to be gene delivery systems. They're really, really good at doing that. Adeno-associated viruses are expressed for a long time—we believe that they express forever—which is something we want for an inherited disease. The virus goes into the cell, infects the cell, then it's over." That, in a nutshell, is gene therapy. Once the corrective copy of the defective gene infects the abnormal cells, genetic information should start processing correctly. In the case of RPE65, that means making a once-missing protein. The surgical procedure to inject the drug requires special technical skill. Currently, the Still, many of his patients were able to see for the first time in their lives, and the trial's success has paved the way for the development of genetic therapy treatments for other inherited diseases. "One of the young girls I treated in Oregon did so well that she invited me to her fourth- grade graduation," Stout said. "She was in the Washington State School for the Blind and she invited me to graduation because they were kick- ing her out. The school threw a big party—they'd never been able to kick anybody out before." Baylor is currently working on additional trials involving other genetic mutations that cause ocular disease, but will continue the research and surgeries that are literally shedding new light on their patients' lives. For Martin, who had the lenses in both eyes removed at age two due to complications from congenital cataracts, that means not wearing glasses for the first time ever. To celebrate, her aunt took her to buy a pair of Ray-Ban aviators, but she's most excited about going back to Disney World. A roller coaster junkie, Martin can now ditch the special goggles with lenses as thick as magnifying glasses. "I'm excited, because I'll actually be able to see the rides this time," she said. therapy can only be administered at eight U.S. sites; Baylor College of Medicine is one of those sites and four surgeons there are trained to per- form the surgery. The first step is the pars plana vitrectomy. Surgeons make micro-incisions through the wall of the eye and use a special hollow needle housing a blade whirring 2,500 times a minute to remove the jelly-like vitreous, which is too viscous to simply suction. Once the PPV has cleared a path to the retina, an even smaller needle—about the circumference of four strands of brunette hair—is used to inject a small blister of Luxturna just underneath the retina. That injection is loaded with the adeno-associated virus carrying the corrected RPE65 gene. Clinical trials showed extremely promising results, although Stout and his fellow research- ers did observe that the treatment worked best in younger patients, perhaps because their cells carrying the RPE65 gene had not yet reached a point of no return. "You probably can't treat dead cells, right? Once you're dead, it's kind of game over," Stout said. "But what we don't know is where in the disease process those cells become fated to never be repaired. So we're expecting that there's going to be a spectrum of susceptibility for gene therapy for different diseases and different genes."

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