Optogenetics: Bringing Light to the Blind

RETINA TODAY (RT): CAN YOU EXPLAIN THE CONCEPT OF OPTOGENETICS?

Vinit B. Mahajan, MD, PhD: Optogenetics began as a lab technique where light (opto-) was used to control genetically modified cells (-genetics) that were engineered to respond to specific wavelengths of light.¹ This technology has now been translated into novel therapeutics to potentially treat patients who have lost sight due to the degeneration of photoreceptor cells.²

Photoreceptors sense light using opsin proteins. In nature, there are thousands of different opsin proteins used by bacteria, algae, fish, reptiles, animals, and even fungi to sense light. Humans have three opsin proteins for color and one for dim light. When photoreceptors die, as in retinitis pigmentosa, there are no opsins left to turn light into an electrical signal.

For human optogenetic therapy, scientists engineer a single new opsin protein to sense light and trigger an electrical signal.² Each optogenetic company has made its own uniquely engineered opsin protein (Table).

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The trick is to turn the surviving retinal cells that normally don’t sense light into light-sensitive cells. The two target cells being used so far are retinal ganglion cells and bipolar cells (Figure). To deliver the engineered opsin, customized gene therapy vectors target these cells, and special cell-specific DNA promoters restrict protein expression to the target cell.

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Figure. A healthy retina has four light-sensing opsin proteins expressed by rod and cone photoreceptors. Patients lose vision when retinal photoreceptors degenerate and opsin proteins are lost. Optogenetics uses gene therapy vectors to deliver single engineered opsins to either retinal ganglion or bipolar cells to make these cells light sensitive and restore sight.

Although retinal ganglion cells were the first cells to be targeted, bipolar cells may have some advantages.³ The number and density of bipolar cells is much higher than retinal ganglion cells, so the theoretical resolution is higher. As for retinal circuitry, bipolar cells are closer to photoreceptors and remain connected and modulated by amacrine cells, so bipolar cells may generate more nuanced signals.

RT: WHAT THERAPIES ARE IN THE PIPELINE AND HOW ARE THEY DIFFERENT FROM ONE ANOTHER?

Dr. Mahajan: At least five companies have created opsin proteins and have started human clinical trials (Table). Each uses its own opsin protein with some type of adeno-associated viral vector delivered by an intravitreal injection, and two require extraocular devices, such as goggles, to focus light and amplify the opsin signal.

Most have targeted retinal ganglion cells, but I expect we will hear more about bipolar cell targeting. In addition, newer engineered opsin proteins that have not yet entered human clinical trials are in development.

RT: HOW IS OPTOGENETIC GENE THERAPY DIFFERENT FROM OTHER GENE THERAPIES?

Dr. Mahajan: There are a lot of similarities between optogenetics and more traditional gene therapy, like injecting a viral vector to deliver a new gene. The main difference is that optogenetics doesn’t replace a defective gene. Optogenetics doesn’t care which gene is not working; it’s agnostic. Instead, optogenetics inserts a new protein (opsin) into retina cells. I think it’s one of the most amazing things happening in medicine today. We are reengineering our tissues with synthetic proteins to restore our most important sense—sight!

RT: WHICH PATIENTS COULD BENEFIT FROM OPTOGENETICS?

Dr. Mahajan: We all have patients in our clinics with advanced retinal degeneration and very low vision—even light perception—where vision loss is caused by photoreceptor cell loss, but the inner retina is preserved. While clinical trials have focused on patients with genetic eye disease, advanced AMD patients with geographic atrophy may also benefit from optogenetics.

RT: WHAT CAN PATIENTS SEE AFTER OPTOGENETIC THERAPY?

Dr. Mahajan: In the first reported case, a patient underwent optogenetic therapy, and when trained to use goggles, they could better identify close objects in front of them (such as a plate or mug) and navigate better (eg, identifying crosswalks).⁴ In other studies, patients demonstrated statistically significant visual acuity gains, visual field expansion, and functional improvements such as avoiding obstacles and identifying differently shaped objects in low light. Anecdotal patient reports include improved face recognition, room navigation, and large object recognition.^5,6

RT: WHAT ARE THE POTENTIAL RISKS WITH OPTOGENETICS AS A THERAPEUTIC APPROACH?

Dr. Mahajan: Although a lot could go wrong, the clinical trials are promising from a safety perspective. Because a nonhuman protein is being put into the body, there is a concern for immune reactions that reject the opsin and immune reactions against the gene therapy vector. So far, local immunosuppression with corticosteroids has been sufficient to address this complication.

Another question is, what happens when atypical cells start sending light signals to the brain? What will the brain see? Will it all be random noise? The recent clinical trials for inherited retinal degeneration and anecdotal patient feedback point to a clinical and functional benefit without visual confusion. As more clinical data comes in, we will gain a better understanding.