Published March 7, 2016
John M. Sullivan, MD, PhD, associate professor of ophthalmology, has received three grants totaling $2.78 million to continue research that could lead to gene therapies for hereditary retinal and macular degenerations.
Sullivan’s research is funded by competitively renewed grants from the National Eye Institute — part of the National Institutes of Health — and the U.S. Department of Veterans Affairs. He is also the principal investigator on a State University of New York (SUNY) Health Now grant.
“This is a time to try to leverage our success to build a more successful gene therapy program and to move our therapies closer to the clinic,” says Sullivan, a clinician-scientist who specializes in retinal degenerative diseases.
Sullivan and his research team are developing gene therapies based on the design of tiny molecular scissors, called ribozymes, which cut specific messenger RNAs in the cell and prevent their use to synthesize proteins that ultimately have toxic effects in retinal cells. Ribozymes are in the class of therapeutics called post-transcriptional gene silencing agents.
“Our goal is to keep retinal photoreceptor cells — which begin the process of vision — viable and functional longer into the lives of individuals with certain retinal degenerative diseases,” says Sullivan.
“I am fortunate to have built an outstanding research team to drive progress in this research area and, hopefully, bring gene therapies into the clinic for patients with these diseases. We are all working very hard and are committed to this effort.”
Sullivan and his team are working toward developing therapeutics for age-related macular degeneration (AMD), a leading cause of vision loss among people 50 and older. Few treatment options are available for those with dry AMD, the most common form of the condition.
“Currently, nonspecific vitamin support is the only approved therapy for dry AMD, but there is no specific therapy for it,” explains Sullivan.
He will use the VA grant to conduct preclinical tests of a novel gene therapy strategy for dry AMD. Success in vivo in mice is an essential first step toward human clinical trials, which could be conducted within the VA health care system, he says.
“AMD is a health care crisis,” he emphasizes. “There are 4 million people in the United States with severe visual disability due to AMD, and this number is expected to triple by the year 2020.”
“AMD prevalence increases exponentially over the age of 55 and, with our aging society, there are many millions of American veterans who will suffer from visual loss due to AMD.”
Sullivan is also an expert on retinitis pigmentosa, a common form of retinal degeneration that causes a progressive loss of peripheral vision and leads to “tunnel” vision. The autosomal dominant forms of retinitis pigmentosa (ADRP) can be caused by mutations in various genes.
Sullivan’s four-year grant from the National Eye Institute, which is in its third renewal cycle, will support his preclinical research and tests of highly potent post-transcriptional gene silencing agents that he developed in his lab.
He and his research team developed the gene silencing agents to rescue retinal degeneration in animal models that are “humanized” by expressing human rhodopsin genes that cause ADRP.
Successfully rescuing retinal degeneration in these humanized animal models of ADRP could lead to therapeutic agents in human clinical trials, he says.
Sullivan is using the SUNY Health Now grant to collaborate with a team of scientists and scholars from four SUNY institutions: the University at Buffalo, Upstate Medical University, the University at Albany and Downstate Medical Center.
He is also working with researchers from institutions including Rensselaer Polytechnic Institute, the Hauptman-Woodward Medical Research Institute and the University of Michigan.
“With our SUNY Health Now grant, we’re taking a therapeutic that was initially grown from our NIH-funded project, and we’re working with very high-end technological developments to optimize that therapeutic,” says Sullivan.
“We’re building information and preliminary data so that our team can apply for a much larger grant from the National Eye Institute with the goal of bringing the therapeutic into the clinic,” he says.
“In everything we’re doing, we’re thinking about translational medicine.”
Sullivan received the SUNY Health Now grant through the SUNY Health Network of Excellence, which is designed to maximize the diverse strengths in biomedical research across the SUNY campuses.
Sullivan mentors trainees from UB’s ophthalmology residency and students from UB’s medical education program. He trains them on retinal degenerative diseases and emerging therapies in the classroom and the clinic.
“My goal is to cultivate the clinician-scientist path — a very challenging path — in my lab,” he says.
Sullivan, who completed an MD/PhD program at Mount Sinai School of Medicine, is dedicated to sharing his research and clinical experiences and successes with medical students and trainees.
“I'm trying to teach them about the kinds of things that are important to maintaining the physician-scientist path and evolving it into a career.”
“I’m interested in building the investigative spirit in medical students and residents. Investigation is really the important thing in learning more about diseases and building therapeutics,” he emphasizes.
The medical students Sullivan trains are involved with the research supported by his grants, and they have opportunities to gain experience in a variety of areas.
Several medical students have recently contributed to research efforts. Fourth-year medical student Dian Yu — who recently matched at Georgetown University for ophthalmology residency — tested a modification of the lead ribozyme and is currently writing a case presentation on a family with a rare hereditary retinal degeneration.
Third-year medical student Beau Froebel is working with Sullivan on a major bioinformatics manuscript focused on gene therapy, and second-year medical student Scott Ketcham has contributed to evaluating a new support RNA for the lead ribozyme.
All three medical students received funding from a summer research fellowship program sponsored by the dean’s office of the Jacobs School of Medicine and Biomedical Sciences.
Three ophthalmology residents — Archana Gupta, MBBS, Steven Tersigni, MD, and Matthew Anger, MD — are currently working with Sullivan on case presentation manuscripts for families with retinal degenerative diseases. Residents that he has trained have presented work at the annual meeting for the Association for Research in Vision and Ophthalmology.
Sullivan notes that UB’s ophthalmology residency is extremely competitive. “We receive about 350 high-quality applications for three residency positions. Out of about 30 interviewees, we select three residents,” he says.
“Having a valuable and productive research experience can contribute to both a deeper understanding of ophthalmology and enhancing the application package for residency.”
Sullivan has built a regional clinical referral service in retinal degenerative diseases at the Ira G. Ross Eye Institute. Patients with diverse retinal degenerative diseases seek clinical and genetic diagnoses and care with emerging therapies.
He also cares for patients with retinal degenerative diseases in the VA Western New York Healthcare System, where he is a staff physician-scientist.
After ophthalmology residency at Washington University in St. Louis, Sullivan spent two years at the University of Michigan in a clinical and research fellowship focused on hereditary retinal and macular degenerative diseases.
Sullivan conducts research with a team that includes Mark C. Butler; Jason M. Myers; Zahra Fayazi, DVM, PhD; Jennifer Breen; Alexandria Trujillo, a doctoral student in the Department of Pharmacology and Toxicology; and Danielle Polniak, a biotechnology student from Rochester Institute of Technology.
“This team has brought a rich multidisciplinary set of expertise to the challenge of developing gene therapies for retinal and macular degenerations,” says Sullivan.