Gene therapies currently under study for retinal dystrophies are administered when viable photoreceptor able to be rescued at the functional level still remain. Most therapies are gene-specific and, in some cases, mutation-specific. In advanced disease stages, when a large number of photoreceptor cells have degenerated, the probability of success of these therapies is very low. Therefore, researchers are exploring methodologies to turn other retinal cells, such as ganglion cells, into light-sensitive cells. This approach is known as optogenetics.
Since only 1% of retinal ganglion cells are photosensitives, optogenetics aims to substantially increase this number by introducing the gene for a light-sensitive protein through a gene therapy vector. The most commonly used proteins are channelrhodopsins from Chlamydomonas green algae. Channelrhodopsins are usually stimulated by blue or red light and when activated they function as a protein-membrane channel, which opens letting ions flow through (usually cations like H+, Na+, K+, Ca2+). The flow of ions generates an action potential, through which the light stimulus signal is transmitted to the brain.
Currently, three different optogenetic strategies are in early clinical phases to restore advanced vision loss in retinitis pigmentosa patients. As retinal ganglion cells that synthesize channelrhodopsin are less photosensitive than photoreceptors, optogenetic therapy is complemented, in some cases, with a portable medical device akin to a pair of glasses to improve visual stimulation. The glasses capture the image with a camera and transform it into adequate visual stimuli for ganglion cells activation.
In 2016 the pharmaceutical company Allergan acquired RetroSense, a pioneer company that developed the first optogenetic therapy for retinitis pigmentosa (RST-001). This therapy uses a modified channelrhodopsin gene administered with a viral vector via intravitreal injection to target retinal ganglion cells. To assess its safety, a first-in-human study with 14 RP patients was started in the United States in 2016. Although no preliminary results have yet been published, Allergan plans to expand the study to 12 new patients to evaluate different doses of the therapy.
GenSight Biologics, a French company specialized in gene therapies for hereditary retinal diseases, has developed another type of optogenetic therapy (GS30), based on a modified channelrhodopsin, also targeting retinal ganglion cells. Since 2018, the safety and tolerability of this therapy has been evaluated in a phase 1/2 clinical trial (PIONNER) with patients with retinitis pigmentosa conducted in the United States, France and the United Kingdom. After intravitreal injection of the therapy, patients must wear a portable optronic visual stimulation device. So far, the therapy has been administered to 6 patients in the two lowest dose groups with good tolerability results. GenSight has also received the go-ahead to administer the therapy to 3 more patients, who will receive the highest dose under study. The results of this study are expected in mid-2021.
Finally, this year the American company Bionic Sight started a phase 1/2 clinical trial of another optogenetic treatment for patients with retinitis pigmentosa with advanced vision loss. The company Applied Genetic Technologies Corporation (AGTC), specialized in gene therapy, has designed the optogenetic strategy and Bionic Sight has developed a device that captures images and recreates the code of ganglion cells stimulation that occurs in normal vision. Bionic Sight plans to recruit a total of 20 patients for this clinical study.
If the expected positive results are obtained, optogenetic therapy would be applied to restore visual function, even partially, in patients with advanced retinal dystrophies, regardless of the gene that is causing the disease. It is important to note that this type of therapy could also potentially benefit patients with medium level of vision and for whom a specific gene therapy has not yet been developed.
[Image: Wikimedia Commons]