A Vision to Restore Sight for Patients with Inherited Retinal Diseases

By Kristen Ashworth

Inherited retinal diseases (IRDs) encompass a diverse group of blinding eye conditions that commonly present in childhood.1 Pediatric patients diagnosed with IRDs face a challenging lifelong outlook: progressive vision loss caused by photoreceptor degeneration, often from the periphery inward (as is the case with retinitis pigmentosa, the most common clinical IRD diagnosis).2 Often, the disease results in irreversible loss of vision and legal blindness.3

Variants in over 300 IRD-associated genes have been discovered. But, of the hundreds of IRD-causing mutations, an effective treatment for all but one IRD has yet to be found—Dr. Brian Ballios has a vision to change that. By developing a novel, pre-clinical, humanized model of disease, he believes the evaluation of stem cell transplantation therapies could be optimized, potentially changing the course in IRD treatment discovery.

Dr. Ballios is an ophthalmologist and clinician-scientist at the Donald K. Johnson Eye Institute at the Krembil Research Institute and Toronto Western Hospital. Before deciding on the field of ophthalmology, he pursued an MD/PhD here at the Institute of Medical Science, where he built on his undergraduate background in engineering to work on a bioengineered approach for the transplantation and delivery of stem cells in human retinal disease. After completing his training in ophthalmology, Dr. Ballios obtained sub-specialty training in rare retinal genetic disorders at Harvard University. He has now returned to his home base in Toronto, where he continues to apply his academic and clinical expertise in rare retinal disease and stem cell biology as a clinician-scientist. The primary aim of his research program is to develop new stem cell-based therapies for IRDs. But, he’s doing it with a new approach—one that can hopefully address some previous challenges in treatment discovery.

Some fundamental stumbling blocks have impeded vision scientists from finding IRD cures in the past. Firstly, the vast molecular heterogeneity and phenotypic variability in these disorders make it inherently difficult to study, define, and elucidate a treatment for any particular IRD. “The patients that I see in clinic who have inherited retinal disorders—no two of them are alike,” Dr. Ballios explains. The second challenge is finding a treatment that benefits patients with advanced photoreceptor degeneration, where most of the retina’s light-sensitive cells have already been lost. In the case of these patients, treatment is likely to be more effective if it can replace cell function altogether rather than attempting to ‘fix’ a pre-existing population of diseased cells.

Stem cell engraftment is one approach that could be particularly beneficial for patients with advanced photoreceptor degeneration. Healthy cells from human donors are injected into a patient’s eye, replacing and repairing diseased photoreceptors. Dr. Ballios explains that the important question then, is “how do donor or transplanted cells interact with IRD-mutated host tissue, and how can we enhance how those [healthy] cells interact with that tissue?”

Traditionally, mouse models have been used to try answering this question. However, some challenges with translatability arise, as animal models are limited in their ability to faithfully recapitulate the molecular and physiological intricacies of the human retina. “We’ve learned a lot from those [animal] experiments. But one thing we haven’t been able to really get at is how healthy human cells and diseased human cells interact.”

To fill this gap, Dr. Ballios and his team are developing a novel, humanized model of genetic disease in which stem cell transplantation can be tested preclinically. His lab uses pluripotent stem cells derived from patients with specific IRD-causing mutations and induces these cells to mature retinal tissue in vitro. The advantage of using these 3D retinal ‘organoids’ is that they closely reflect the human condition. To evaluate stem cell transplantation therapies, Dr. Ballios explains that healthy human stem cells can be added to the diseased organoid model, and cell survival and integration can then be monitored as the organoid matures. With downstream analysis of retinal development markers and by tracking morphological changes, Dr. Ballios hopes to gain new insight into donor-host cell interactions and the rescue efficiency of healthy cells on diseased photoreceptors.

Dr. Brian Ballios, MD, PhD, FRCSC, DABO

Assistant Professor, Department of Ophthalmology and Vision Sciences at the University of Toronto;Clinician-Scientist, Donald K. Johnson Eye Institute; Associate Member, Institute of Medical Science

Photo credit: Niki Akbarian

Children with IRDs have yet to accumulate the degeneration that comes with aging and thus typically retain a larger population of photoreceptors than the adults that Dr. Ballios sees in his clinic. Therefore, the necessary potency of a cell replacement therapy will differ between patients. A personalized approach is needed, and this requires experimenting with the proportion of healthy cells needed to be transplanted at varying stages of degeneration.

The end goal of the work in the Ballios Lab is to optimize stem cell engraftment therapies tailored to patients with specific types of IRDs and target these therapies for specific stages in disease progression. As Dr. Ballios points out, an effective treatment is “not just about identifying the right patient with the right disease, but also the right patient with the right disease, at the right time in their life.”

In the clinic, Dr. Ballios has seen first-hand the impact a cure can make on a patient with an IRD. He recounts a recent visit to his clinic by a pediatric patient with an IRD-causing mutation in the RPE65 gene. Fortunately, RPE65-related disease is the one IRD in which there is a Health Canada-approved gene therapy, known as Luxturna® (voretigene neparvovec-rzyl). Though it comes with a large price tag, Luxturna® is a one-time treatment that can stop adverse vision loss and restore visual function in patients with RPE65related IRD—a miracle drug for a patient otherwise progressing toward blindness. “Telling that young girl and her parents that there’s actually a gene therapy for that disorder, and there’s a treatment that can stabilize or regenerate her vision—that was incredible,” Dr. Ballios says.

Dr. Ballios emphasizes that perseverance is key to finding more cures and continuing to provide newfound hope for patients with IRDs. Just as much as he is inspired by the perseverance of his patients, he hopes he can pass that perseverance on to inspire others too particularly trainees, who play a vital role in moving the field forward. “I hope I can help encourage graduate students to continue to follow their passions in research and medicine because many hands make light work. And we need that, we need more people,” Dr. Ballios reflects. “Research is not a straight line, and the path to cures is not a straight line. There’s discouragement along the way, there are successes and failures. But it’s important to stick with it,” he says. “That’s probably the most important lesson I’ve learned in the early part of my career.” Perseverance to do whatever it takes—a powerful fueling agent that drives his visions forward and empowers others to do the same.

To learn more about Dr. Ballios’ research, please visit www.ballioslab.com.

References

1. Georgiou M, Fujinami K, Michaelides M. Inherited retinal disease:Therapeutics, clinical trials and end points—A review. Clinical &Experimental Ophthalmology. 2021Mar20;49(3):270–88.2. O’Neal TB, Luther EE. Retinis Pigmentosa. In: StatPearls [Internet].Treasure Island, FL: StatPearls Publishing; 2022.3. Martinez Velazquez LA, Ballios BG. The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease. Inter-national Journal of Molecular Sciences. 2021Nov26;22(21):11542.