A Eureka Moment for Paul Yang Boosts Advancement of Vision-Saving RP Drug
His latest Foundation grant is helping move the drug toward a clinical trial
Early in his clinical research career, Paul Yang, MD, PhD, received a Foundation Fighting Blindness clinical research fellowship award to evaluate a drug called mycophenolate that showed the potential to save vision for many people with retinitis pigmentosa (RP), regardless of the gene mutations causing their vision loss. He’d previously used the drug, already FDA-approved for other conditions, for uveitis (an inflammatory eye condition), and felt optimistic he’d had a good treatment candidate for RP.
Vision loss for many people with RP and other inherited retinal degenerations is caused by the accumulation of a molecule called cyclic guanosine monophosphate (cGMP). While cGMP is an important messenger molecule for converting light into electrical signals in the retina, too much of it is toxic. Mycophenolate can help regulate cGMP, thereby reducing the toxic accumulation.
“Mycophenolate is one of several medications we use a lot when trying to control inflammatory disease in the eye, but it is the only one that inhibits the pathways that are also specific to cGMP accumulation,” says Yang. “We’ve used it off label for treating uveitis for decades. We have a good idea of how to use it for eye conditions.”
But his pilot experiments with mycophenolate weren’t working. “I was a week away from the end of my fellowship and was prepared to put my project aside and move on,” he recalls. “I decided to give it one more try.” In his initial experiments, he reared the mice in darkness. Doing so, Yang hypothesized, would slow degeneration and give the drug more time to work. But working in the dark had been tedious, so he decided to try one more experiment with the mice reared in normal light, even though, from a scientific standpoint, it didn’t make sense to him. With that lighting change, the treatment worked.
“It was one of those Eureka! moments in science that make all the other failures worthwhile,” says Yang. “Just because it doesn’t make sense doesn’t mean it is not worth investigating further. Sometimes we just don’t understand the science very well, and we learn more when unexpected things are observed.”
Yang used the data from that study to get a subsequent Foundation Fighting Blindness career development award, which supported additional experiments to confirm the original results. Recently, Yang received a $900,000 Foundation translational research acceleration program (TRAP) grant to move the therapeutic approach toward a clinical trial. The TRAP grant is enabling him to select a lead treatment candidate and test it in additional mouse models. Given that mycophenolate and the other drugs being evaluated are already clinically approved, the time needed for safety and toxicology studies in preparation for a clinical trial in inherited retinal degenerations is likely reduced.
Yang came to Casey Eye Institute, Oregon Health & Science University (OHSU), for an ophthalmic genetics fellowship in 2012 after completing his ocular immunology fellowship at Massachusetts Eye Research & Surgery Institution (MERSI), and internship and residency at Moran Eye Center, University of Utah. He subsequently stayed on at OHSU as faculty.
Yang’s timing for joining Casey was exquisite with the advent of gene therapy clinical trials for many inherited retinal diseases. Today, he is the lead investigator on eight clinical trials, including Applied Genetic Technologies Corporation’s (AGTC) X-linked RP gene therapy study, 4D Molecular Therapeutics’ X-linked RP gene therapy study, ProQR’s CEP290 and USH2A RNA therapy studies, and Stargazer’s study of its drug for Stargardt disease. He is also a co-investigator on 13 other human studies and sees patients in the clinic.
Yang was inspired to get into science and ophthalmology by his father, an electrical engineer, as well as his biology studies in school. He says, “During my education, I realized that the retina is the most complex, highly organized system in the body. It is essentially a 3D circuit that turns light into electrochemical signals. It is actually a part of the brain — the only part of the brain which the doctor can see with the naked eye in the clinic, and by doing so, can diagnose and treat conditions.”
Yang shares his passion for ophthalmology with his wife, who is a pediatric ophthalmologist at Casey. They met when they were both in training at Moran. “We share information and refer patients to each other over dinner,” he says. “A patient can only hope their two specialists are married.”
Yang is grateful to his many mentors — including Richard Weleber, MD, Mark Pennesi, MD, PhD, Catherine Morgans, PhD, and Robert Duvoisins, PhD, from Casey, C. Stephen Foster, MD, from MERSI, and Paul Bernstein, MD, PhD, and Albert Vitale, MD, from Moran — all of whom helped him get grants and advance his career.
Yang also says that support from the Foundation has defined his clinical and research careers. “Without the Foundation, none of this would exist. I would be somewhere else doing something else.”