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With the publication of findings from their optogenetics study (PIONEER clinical trial) in May in Nature Medicine detailing the initial success of the partial restoration of vision in a patient with retinitis pigmentosa, the international multicenter collaborative study achieved an important milestone in vision restoration from retinal blindness with a novel light activating retinal gene therapy.
The study was led by an international team of researchers, including José-Alain Sahel, MD, chair of the Department of Ophthalmology at the University of Pittsburgh and director of the UPMC Eye Center, who has spearheaded this and many other novel vision restoration approaches and is the culmination of more than two decades of painstaking research by multidisciplinary collaborators in Europe and the United States. Joseph N. Martel, MD, assistant professor of ophthalmology at UPMC Eye Center is a principal investigator at the only U.S.-based clinical trial site of the study. Joining Drs. Sahel and Martel in the research were Botond Roska, MD, PhD, of the Institute of Molecular and Clinical Ophthalmology Basel, and colleagues from GenSight Biologics and the Institut de la Vision, both in Paris, France.
The magnitude of the study's findings is immense, and the future clinical implications of this work are theoretically far-reaching for many types of retinal diseases that rob their victims of their sight – sometimes slowly, sometimes very rapidly – diseases which at present have few or no treatment options.
“Our initial findings are robust and very encouraging,” says Dr. Sahel. “But the research is far from over. Our team is enthusiastically moving forward with our studies.”
Dr. Sahel's team in the future will likely examine the feasibility of using different light-sensing proteins in their gene therapy approach. It is possible that more sensitive proteins can be engineered in the future, ones that may have a response to light across a broader spectrum of the visible range for humans or proteins that require fewer total photons to stimulate their activity. Proteins may be modified so that they can express or accept a wider dynamic range of light-sensing capabilities, and the light stimulating goggles that are currently required as part of the therapy may go through iterative engineering phases to improve their capabilities, a process that has already occurred in order to enhance the edge detection capabilities of the camera systems in the device.
"It is important to realize that our current PIONEER study is an early phase clinical trial to evaluate safety and efficacy. This is the beginning, but as our findings show, we see much promise for this therapeutic approach. Our PIONEER trial is ongoing. We are evaluating other subjects that were enrolled in the study and who received higher doses of the gene therapy product," says Dr. Martel. "We are also actively studying the long-term effects in terms of both efficacy and safety. Successes in these aims will be crucial to advance our trials in the future and expand upon the findings. Our post-treatment vision assessments were derailed a bit due to the COVID-19 pandemic, and while not thrilled by the delays we have experienced, we are hopeful that our studies will resume in a more normal fashion as the pandemic is curtailed."
For example, it is not known at present if multiple injections of the gene therapy are required over time to maintain efficacy or response or if a single dose and its effects can persist over many years or decades.
"Of course, we receive many questions about how fast the work will progress and be translatable to the clinic, and in what ways we can layer on or add to a complete restoration of vision, for example, with color vision, or whether or not the goggles that our subjects currently wear in our studies will always be required with this type of therapy. The answers, of course, are that we are not sure. Our priority right now is to continue with the current line of research studying the safety and efficacy of the regimen, the durability of response over time, and working to increase the visual acuity and dynamic range that our therapeutic approach seems to offer," says Dr. Sahel.
The long-term clinical implications of this research are unambiguous: a person who has lost the ability to see or a portion of their sight can in some respects see again. Perhaps it will turn out that only portions of vision can be restored through this type of therapeutic approach, or the restoration of the full experience of what is considered "normal" vision may not be achievable for many generations, or that only some patients will have responses to the therapy. These are all unknown or hypothetical questions, but they do not detract from the monumental achievement Drs. Sahel, Martel, and colleagues have brought to the world, one that eagerly awaits news of their progress and continued success.