Bascom Palmer’s Research Center for Inherited Retinal Diseases

Mark J. Daily, M.D., is dedicated to finding new treatments for inherited retinal diseases that steal vision from children and adults. “We need laboratory studies and clinical trials to advance our understanding of these genetic disorders,” said Daily, a retinal specialist in Wheaton, Illinois, who completed his residency at Bascom Palmer in 1977. “Bascom Palmer is in the forefront of genetics, stem cells, and imaging, making it a natural location for a new center.” translational research with a superior patient experience.”

Since the 1990s, Bascom Palmer has built an extensive gene therapy program that includes ophthalmologists and research scientists studying various forms of inherited eye diseases, said the center’s director Byron L. Lam, M.D., professor of ophthalmology, the Mark J. Daily Chair in Ophthalmology, and the medical director of clinical research. “We have a large pool of patients whose genes have been linked to specific disorders,” said Lam. “We also have an excellent infrastructure with novel imaging techniques and instrumentations that will contribute to our basic science and translational research.”

A challenging landscape

Inherited retinal diseases (IRDs) affect millions of people globally, reducing vision and causing blindness. There are more than 300 types of IRDs, which usually result from a mutation in one or more genes that code for a retinal protein. These rare blinding conditions include X-linked retinitis pigmentosa (RP), achromatopsia, choroideremia, Leber congenital amaurosis, Leber hereditary optic neuropathy, X-linked retinoschisis, and Stargardt macular dystrophy.

Now, the longtime Illinois ophthalmologist is bringing renewed hope to patients and families with the opening of the Mark J. Daily Inherited Retinal Diseases Research Center at Bascom Palmer. By providing a home for scientific research, clinical trials, patient care, and medical education, the new inherited retinal disease center will usher in a new era for the Institute’s growing team of retinal specialists.

“Thanks to the extraordinary philanthropy of our alumnus Dr. Mark J. Daily, Bascom Palmer will have a renowned center where cutting-edge inherited retinal diseases research is conducted and enhanced,” said Eduardo C. Alfonso, M.D. “The center will allow us to multiply the output of research and clinical trials in inherited retinal diseases, and we will integrate

Because of the complexity and rarity of most IRDs, the Institute’s new center will play a key role in focusing scientific and clinical research on gene therapies. “Even though traditional gene replacement therapy is very powerful, it can only treat one mutation at a time,” said Vittorio Porciatti, D.Sc., professor of ophthalmology, vice chairman of research, and the James L. Knight Professor in Ophthalmology. “Therefore, our basic science program is generating in-house therapies that are gene agnostic. By targeting pathways common to many mutations, we could develop one therapy that is effective against multiple mutations.”

Lam said the Daily Center will advance translational research in the treatment of IRDs that will lead to clinical trials in a reasonable time frame. “The new endowment will support early-stage studies, which can hopefully draw funding from government agencies as well as industrial partners,” he said. “New research could aid in the rapid identification of these complex conditions and one day might halt the progression to blindness or lead to sustained improved vision.”

A long history

Bascom Palmer has a long history of treating IRDs. The Institute’s founder, Edward W.D. Norton, M.D., had a clinical and research interest in retinitis pigmentosa, as his wife and son lost their vision from this blinding disease. In 1983, Norton recruited Samuel G. Jacobson, M.D., Ph.D., to establish a research and clinical center for retinal degeneration. In his 12 years at the Institute, Jacobson established a highly productive multidisciplinary research program investigating the mechanisms of retinal degeneration.

Over the past 20 years, the Institute has conducted numerous studies funded by the National Eye Institute. Lam said the achievements thus far of identifying genes and biomarkers associated with mutations furthered the testing of clinical gene therapies for a spectrum of inherited retinal diseases.

In addition, John R. Guy, M.D., Bascom Palmer professor and holder of the Rodgers Research Chair in Ophthalmology, conducted pioneering gene therapy research for the treatment of Leber hereditary optic neuropathy (LHON), optic neuritis, multiple sclerosis, and other diseases caused by mutations in mitochondrial DNA.

Before he died in 2020, Guy developed a novel technological treatment for LHON. By successfully modifying a virus, he was able to introduce healthy genes in the mitochondria to correct the genetic defect. His research demonstrated the immense potential for gene therapy applications to treat other blinding and life-threatening conditions. As Lam put it, “We are all standing on his shoulders.”

Giving back to the Institute

Reflecting on the 1970s, Daily has fond memories of his training at Bascom Palmer. “Working with Dr. Norton and other pioneers in ophthalmology was the highlight of my educational experience,” he said. “I was fortunate to be there when the faculty members were pioneering vitrectomies and ocular lens implants, as well as making major advances in glaucoma, corneal and retinal procedures.”

In the past few years, Daily, who is also a clinical professor of ophthalmology at Loyola University Medical Center, has paid increasing attention to IRDs. “When I was in medical school, our genetics course was very basic,” he said. “Since then, we have learned a tremendous amount about the human genome and genetic testing can identify most of the mutations. Now, we need to take the next step and develop effective treatments.”

Daily knows that understanding the genetics of the eye can provide insights into other medical problems. Two years ago, he saw a 60-year-old wheelchair-bound diabetic patient who came to his office with her daughter. After a careful eye examination and blood testing, he found she had a rare genetic condition called MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms). “It was an important finding for her and her daughter, who inherited the genes,” Daily said. “The more we learn about IRDs the more we can unravel those types of medical mysteries.

Delivering clinical care

Today, the Institute has one of the largest gene therapy programs in the nation with additional clinical trials and studies coming soon. “Our patients are seen by clinicians who can diagnose inherited eye disorders,” Lam said. “Genetic testing and careful evaluation are necessary to determine if these new therapies are appropriate for individual patients.”

In gene therapy, a tiny dose of adeno-associated virus (AAV) is used as a transmission vector to carry functional new genes into the retina. Once delivered, the new genes use the body’s cellular mechanisms to produce functional proteins with a therapeutic impact on the retinal cells. Every step of the process has to be carefully managed for patient safety and maximum efficacy of the treatment. The Institute’s multidisciplinary support for gene therapy includes the research pharmacy of the Sylvester Comprehensive Cancer Center, which stores the therapeutic vectors at -80 degrees Fahrenheit and delivers them to the operating room just in time for the procedures.

“We spend a lot of time planning cases, beginning with a comprehensive study of the patient’s retinas,” said Janet L. Davis, M.D., professor of ophthalmology and holder of the Leach Chair in Ophthalmology. Advanced imaging technology, including optical coherence tomography (OCT) and fundus autofluorescence, is used to determine if a patient is a suitable candidate. Next, the surgical team carefully maps the patient’s retina to determine precisely where to apply the gene-changing vector. For patient safety, only one eye is treated at a time.

Ninel Gregori, M.D., professor of clinical ophthalmology and chief of eye care services at the Miami Veterans Affairs Hospital, typically works with Davis on gene therapy surgeries on adult patients, while Audina M. Berrocal, M.D., a pediatric retinal surgeon and professor of clinical ophthalmology, operates on children. In 2018, Berrocal operated on a 9-year-old, one of the first persons in the United States to receive an FDA-approved gene therapy treatment.

During the Institute’s first gene therapy trial in 2015, the team integrated OCT imaging into the surgery and shared the results with other surgeons. “We have evolved since then, learning how to do injections more safely and efficiently,” Gregori said. “Industry partners have responded as well. We started with our own injection tubes, and we now have a commercial cannula for these procedures.”

Since the FDA approval of voretigene (Luxturna) in 2017, Davis and Gregori have used subretinal and intravitreal injections to treat adult patients with retinitis pigmentosa, Leber congenital amaurosis, and other diseases. “We are a great team, and we all contribute to each other’s development,” said Davis. “Going forward, we plan to expand our training program and teach ophthalmologists around the world to do these complex surgical procedures.”

“When I met Mark Daily at a dinner several years ago, he had a big vision for advancing retinal care,” said Davis. “Now, having a dedicated, patient-focused center will help families feel comfortable here while providing support for recruiting additional scientists and clinicians. We are entering a new era in genetic medicine, and this is a brilliant way for us to help patients with IRDs.”

Jesse D. Sengillo, M.D., who is currently completing his vitreoretinal surgery fellowship, is also looking forward to the new center. “My mother is affected by an IRD, which sparked my interested in ophthalmology,” he said. “I feel very fortunate to see the advances our field is making in real-time, particularly at Bascom Palmer. The Daily Center will provide state-of-the-art care for patients and facilitate research that brings innovative treatments to the bedside.”

Sengillo is also collaborating with investigators at the Institute on several projects, such as assessing how the location of mutations in particular genes relates to the risks of complications in inherited vitreoretinopathies. “The more we understand about the genes that cause IRDs, the better we can prognosticate for patients and identify candidates for treatment in the future,” he said.

Reflecting on Daily’s support, Berrocal said, “Having a center dedicated to an integrated approach to genetic eye disorders is essential to the future of eye care. Before, we had no cure for pediatric IRDs and blindness was many times inevitable. Now, we can identify and treat certain diseases at an early age for better outcomes. With gene therapy, the future is limitless.”

Advancing laboratory research

Through the years, Lam has participated in more than 25 clinical trials in hereditary retinal diseases including gene therapy, stem cell, and other novel treatments. He also initiated the first U.S. clinical trial in choroideremia gene therapy.

Now, Lam is looking forward to the opportunity to bring more laboratory findings into the U.S. Food and Drug Administration (FDA) pipeline for clinical trials.

“We plan to generate our ideas, gain funding for initial studies, and move forward into larger-scale studies,” he said. “We have also developed new endpoints by using new imaging techniques and a novel way of measuring light sensitivity.”

Several treatment strategies are currently being examined, including gene replacement and stem cell therapies, as well as delivering light-sensitive proteins into the residual retinal cells, Lam said. “We are also looking at RNA-based therapies using antisense oligonucleotides,” he added. “Our goal is to bring meaningful vision benefits to individuals living with inherited blinding disorders.”

For 20 years, Abigail Hackam, Ph.D., professor of ophthalmology, has been working on experimental models of IRD to better understand how inherent mutations lead to photoreceptor death. “We are also using advanced retinal imaging techniques to follow patients over time,” said Hackam. “We have a great collaborative approach that allows us to identify patients and enroll them in clinical trials. It is exciting to have a new IRD center that can translate basic scientific discoveries into potential therapeutics.”

Rong Wen, M.D., Ph.D., professor of ophthalmology, has been studying retinitis pigmentosa for decades. Because RP has more than 200 mutations in 60 genes, Wen is looking for mutation-independent neuroprotective therapies in collaboration with other researchers. “Neuroprotection by CNTF also affects the electroretinography (ERG) amplitudes. ERG is considered a surrogate functional test for the photoreceptors though the ERG effect raised a concern,” he said. “We proved that the ERG effect is a natural effect similar to the retinal response to habitate light. If you put animals in an environment with strong background light, the ERG gets smaller.”

“Retinitis pigmentosa is a long-term disease that is very difficult to treat,” Wen said. “It can take years for a clinical trial to produce results, making it difficult for pharmaceutical companies to invest in such a long timeline. Having the new Daily center here assures us that the IRD research will be here to stay over the long term. After all, it’s worth waiting for good things like effective new therapies for these inherited diseases.” 