The Path Toward Vision Restoration Through Optogenetic Therapy

In May 2021, an international multicenter research team, co-led by José-Alain Sahel, MD, UPMC Eye Center director and Distinguished Professor and Chair of the Department of Ophthalmology at the University of Pittsburgh School of Medicine and by Botond Roska, MD, PhD, of the Institute of Molecular and Clinical Ophthalmology Basel, published revolutionary results of their optogenetic therapy clinical trial, which demonstrated for the first time the partial restoration of vision in a person who lost their sight as a result of retinitis pigmentosa. Collaborating with Dr. Sahel and Dr. Roska on the study were colleagues from the Institut de la Vision and GenSight Biologics, both located in Paris, France.

The results of the landmark study were published in the journal Nature Medicine only a few months ago. However, the work itself is the culmination of nearly two decades of research, persistence, and international collaboration. 

"Me and my long-time collaborator Botond Roska became interested in the potential of light-sensitive proteins from algae to restore or confer light sensitivity to the damaged retina more than 20 years ago," says Dr. Sahel. "It was an interesting proposition that we could potentially harness the power of these proteins and restore vision or aspects of visual perception in some way. We knew it would be a difficult task with the potential for failure, but we are a persistent group not easily deterred.”

Dr. Sahel’s work with optogenetic therapies and technologies is but one part of a larger research platform that revolves around three primary areas of study related to retinal diseases and degeneration: curative therapies and techniques to allow individuals who have lost their ability to see due to retinal disease (gene therapies); neuroprotective strategies to stave off or mitigate the effects of blinding retinal diseases; and restorative approaches to replace damaged retinas or portions of the retina with stem cell therapies, optogenetics, or artificial retina (see Dr. Sahel’s work with the PRIMA clinical trial using an implantable wireless subretinal chip for use in age-related macular degeneration.)

Optogenetic therapy is a novel vision restoration approach that confers light sensitivity to nerve cells in the retina, nerve cells whose primary native function is signal propagation rather than light detection. While the idea of harnessing the light-sensitive proteins from algae to restore vision might seem simple to some,  the challenges and complexities of this approach were many and significant. These proteins are not native to human physiology, and using a foreign protein within the human body requires strict safety testing.

"Another complexity we had to overcome is the truly massive amount of light that is needed to activate these algae-based light-sensitive proteins and achieve a response in their native state. To trigger a response, a person would have to stare at the amount of light comparable to the blazing sun for a significant amount of time,” says Dr. Sahel. “Clearly, that would not be feasible or safe, or within the realm of normal vision, so we needed to find proteins that could be engineered or adapted to require significantly less light to become active. Fortunately, there was work being done on this by Roger Tsien in California, and a group at MIT working along similar lines to enhance these proteins to require less light.” 

Another hurdle to using these light-sensitive proteins in the human retina is that they are sensitive to light within a very narrow band of the visible spectrum. In the protein used by Dr. Sahel and colleagues, the ChrimsonR channelrhodopsin protein responds to light in the range of 580-590 nanometers (amber light). Normal human vision covers a much broader spectrum, so using just this one protein would only confer vision in a limited way in a limited part of the visible spectrum. 

The human eye and retina have the capacity to sense light along a continuum of 12 log units of dynamic range. The light-sensitive proteins used by Dr. Sahel and colleagues in their optogenetic therapy are sensitive to only 2 log units of range, which is many times exponentially smaller.

“One way around these limitations was to use a device – light stimulating goggles fitted with a specialized camera to capture the light from the environment and send a monochromatic beam to the retina at the exact wavelength and intensity needed to stimulate the proteins,” explains Dr. Sahel. "By using the goggles, we could cope with the log unit discrepancy, but then our thought was why not try to better optimize the signal from the goggles with enhanced edge detection capabilities and sensitivity to light that can mimic how the retina functions by detecting changes in light on a pixel-by-pixel basis.”

The type of vision that will be restored with the therapy would be different from the vision the patients would have experienced before being blinded by their disease, so Dr. Sahel and colleagues had to devise a protocol for training and rehabilitation for the subjects participating in the trial.

Thus, Dr. Sahel and his colleagues’ optogenetics therapy for vision restoration is really a three-phased approach. First is the engineering and delivery of the gene carrying the modified light-sensitive proteins to its target at the retinal nerve cells, the retinal ganglion cells. The second was the design and engineering of the specialized goggles to capture and transmit the light into the eye and upon the retina. And third, training the study participants on how to function and learn what the experience would entail and the characteristics of the restored visual perception.

These were no small achievements. The initial preclinical studies, followed by animal model data in nonhuman primates, took years but ultimately provided robust data to support both safety and efficacy trials in human subjects, which began in earnest five years ago and culminated with the findings outlined in the Nature Medicine paper in May.

Interestingly, the subject reported in the Nature Medicine paper received a dose of the engineered proteins at the lowest of the three levels provided during this first safety and dose-escalation study. So far, the durability of the therapy has persisted with time.

More data from Dr. Sahel and colleagues will be forthcoming from the study relative to the progression of the first cohort of enrolled patients, how those subjects who received higher doses of the proteins have fared, and how the studies will evolve in the future.

"Unfortunately for our research team, the COVID-19 pandemic impacted our study. We lost time, but certainly, we have not lost motivation or intensity in our work. I know the entire team is excited to continue this work with our patients in earnest as the effects of COVID-19 on the global community begin to recede," says Dr. Sahel. "We have made tremendous progress during the last two decades with this research and have accomplished something that has never happened before. However, in reality, these are the first steps in a much longer journey, one that I am hopeful someday will help restore normal vision or be as close to it as we can achieve for our patients. Imagine the patient who being blind for decades slowly being able to see again. At first rough shapes and then gradually the details and acuity improve. Imagine that experience for that person and what that would mean. That is why I do this work. That is why we persist in our pursuit."

Further Reading

Read a summary article and watch a video of the research findings at Inside.UPMC.com.

Full findings from the study published in Nature Medicine can be found using the following reference and link:
Sahel JA, Boulanger-Scemama E, Pagot C, Arleo A, Gallupi F, Martel JN, Esposti SD, Delaux A, de Saint Aubert JB, de Montleua C, Gutman E, Audo I, Duebel J, Picaud S, Dalkara D, Blouin L, Taiel M, Roska B. Partial Recovery of Visual Function in a Blind Patient After Optogenetic Therapy. Nat Med. 2021 May 24. Epub ahead of print.

Learn more about Dr. Sahel and his research and how the UPMC Eye Center pushes vision protection and restoration research boundaries through gene therapy approaches, implantable devices, stem cells, and next-generation imaging techniques.