Retinitis pigmentosa (RP) is a genetic disease where cells in the retina called rods and cones slowly die off leading to diminished sight or complete blindness. Rod and cone cells, collectively called photoreceptors, absorb light and convert it to electrical signals. The electrical signals are transmitted through other intermediate cells and eventually pass to retinal ganglion cells (RGCs) which carry the signal to the brain. In the brain, the signals from the RGCs are processed into what we call vision. As the photoreceptor cells die, there is no way to capture the light and communicate it to the brain. Ultimately, the field of vision contracts leaving the patient in near or total blindness depending on how many photoreceptors remain. Over 50 genes have been implicated in this disease with mutations in any of these 50 genes leading to some degree of RP. RP is rare but is still estimated to affect about 2 million people worldwide.
To date, there is no preventative, no therapy, and no cure for RP, but at last, there is some significant hope for ameliorating this debilitating condition using optogenetics. Optogenetics was developed by neuroscientists in the early 2000s as a tool to study brain function. The technique uses a family of proteins, called opsins. Many different opsins have been identified in various species and their genes have been cloned for use in research studies. To introduce the opsins into a cell, the opsin gene is cloned into a viral vector and the recombinant virus is used to infect the target cells. Once inside the cells, the delivered gene is transcribed into messenger RNA (mRNA) and the mRNA is translated into the opsin protein. Opsins insert themselves into cell membranes and respond to light by creating electrical signals. When the light stops the signal stops, similar to the process that occurs in photoreceptor cells. Each opsin responds to a specific wavelength of light, so by choosing a particular opsin and a corresponding light source there can be precise control of signal generation. Over the last 15 years, numerous research studies in rodents and primates have shown that optogenetics is a safe and efficient way to turn on and off electrical signals in nerve cells in response to light stimulation.
A recent paper in Nature Medicine reports the first application of optogenetics to treat RP in a human patient. The patient was a 58-year-old male who was functionally blind but did retain some ability to perceive light. One eye of the patient was injected with an adeno-associated virus (AAV) expressing a cloned opsin called ChrimsonR. This approach targeted the opsin to the retinal ganglion cells (RGCs) to make them directly responsive to light without the need for photoreceptor cells. No inflammation or other adverse effects were detected in the patient’s treated eye. After 4.5 months to allow accumulation of ChrimsonR in the RGCs, the patient began training with specialized goggles. The goggles captured ambient light and converted it to light signals specific for ChrimsonR. After 7 months of training, the patient reported visual improvement. He could now recognize some small everyday objects, find furniture in a room, and recognize a doorway in a corridor, all of which he was unable to do before treatment. Even though his vision was still very limited, it was a dramatic improvement in ways that enhanced his mobility and quality of life. Interestingly, EEG studies showed that the visual cortex of the patient’s brain was responding similarly to normal vision. This suggests that the RGCs had learned to transmit the signal from ChrimsomR stimulation to the brain in the same way they would have transmitted the signals from the photoreceptor cells. While this study was only one patient and there was nowhere near restoration of full sight, these results are an amazing confirmation of the potential power of the optogenetic technique. Engineered improvements in opsins and more efficient delivery to RGCs could someday yield high-quality vision restoration for RP and other eye diseases, even without goggles.