A New Gene Therapy Helps a Blind Man See Light Again

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Issue 17, Volume 111

By Andy Chen 

A 58-year-old afflicted with blindness sees light and images for the first time in 40 years after being treated with optogenetics, a new type of gene therapy.

A Nature Medicine study described the first clinical use of optogenetics, a technique that uses light to manipulate gene expression and neuron activity. The technique was originally developed to probe the functions of the brain and neural circuitry, but recent investigations have revealed that optogenetics can be a potential treatment for brain and blindness conditions.

A common misconception is that blind people see complete and absolute darkness. This is not necessarily true, as only about 18 percent of people with severe vision impairment are categorized as completely blind, and most, at the very least, retain the ability to perceive light. This means that though they cannot see shapes, colors, or people, they can still tell whether it is light or dark. Those who are categorized as legally blind often suffer from a number of conditions that cause low vision in an individual. This includes retinitis pigmentosa (RP), a progressive, blinding genetic disorder that targets and kills photoreceptors in the eye. RP causes tunnel vision, where the field of view is diminished and the person is left with a narrow center of vision.

A healthy retina contains two types of photoreceptors: cones and rods. Cones are responsible for vision at higher light levels, while rods detect light at low light levels. These photoreceptors allow the retina to respond to both high and low levels of light, which are converted into electrical signals and relayed to ganglion cells (GCs). GCs are present in the last layer of the retina and are responsible for processing and transmitting visual information to the brain. Unlike in healthy retinas, cones and rods gradually die in the RP retina, which leads to nonfunctional photoreceptors. As a result, response to light and transmission of signals is disrupted, leading to the visual impairments seen in RP patients. Clinical trials conducted by French firm GenSight Biologics registered people suffering from RP and then developed and tested a new optogenetic therapy that completely disregards the affected photoreceptor cells, the beginning process in the visual pathway. Instead, it uses adeno-associated virus (AAV), a non-pathogenic, genetically altered virus that does not integrate its genome into the human genome, to deliver instructions for the creation of light-sensitive proteins into the GCs, which allows them to directly detect and respond to light and images.

Previous versions of optogenetic therapies used channelrhodopsin-2, a light-sensitive protein found in algae, to help nerve cells respond to light. However, the protein requires a substantial amount of blue light to activate, which could further damage cells in the retina rather than help recover vision. José-Alain Sahel, an ophthalmologist at the University of Pittsburgh Medical Center, proposed using a different type of protein that reacts to amber light, which damages the cells in the retina significantly less compared to green or blue light.

However, Sahel’s group was presented with another challenge. They had to replicate the healthy retina’s ability to perceive a broad range of light by monitoring the amount and kind of light that enters the eye. To do so, the group of researchers engineered special goggles that gathered the light around the individual and adjusted them so that the injected protein could recognize it. The goggles use a specialized camera that examines changes in contrast and brightness of light in the patient’s line of sight and modifies the level of amber light that is sent to the GCs accordingly. Lastly, the goggles send pulses of amber light to activate the GCs that then shoot a signal to the brain and create a visual image.

A man who participated in the clinical trials took several months practicing with the goggles before his brain adapted to translate the pulses of light into visual images. His brain was essentially learning a new language, as it had to create images from a new pathway. Eventually, his brain grew accustomed to the amber light, and he was able to recognize objects and the white stripes on crosswalks. Surprisingly, when researchers analyzed his brain activity as he saw the images, they concluded that his visual cortex performed identically to the way it would have reacted if he had normal vision.

Sahel’s team had previously designed a set of tests that assessed the effectiveness of the injection, for instance discerning, locating, and touching an object on a table. Before treatment, the man was unable to discern the object and therefore, was unable to locate or touch it. After treatment, he was able to discern objects 64 percent of the time, locate them 64 percent of the time, and touch them 57 percent of the time. Additionally, he was able to count objects successfully 63 percent of the time, which he could not do before treatment. But when the goggles were removed, his improvements in vision would vanish as well, leaving the man with pretreatment levels (zero percent). While the man still requires the goggles to see or make out shapes and colors, his vision has clearly improved since he last received the injections two years ago. Six others also received the same treatment, though the COVID-19 pandemic has postponed their practice with the special goggles.

Because the retina contains many times more photoreceptors than the GCs focus on in this treatment, the GCs will never be able to produce high-quality images as natural vision does. However, the fact that the treatment is safe and permanent is extremely encouraging.

GenSight is just one of many companies exploring optogenetics as a treatment for RP. A company named Bionic Sight reported that some RP patients treated with a similar optogenetic therapy and a virtual reality set partially recovered vision. Another company, Novartis, announced that it developed an optogenetic therapy that uses an even more light-sensitive protein where special goggles may not be required.

While the treatment is not a cure, as it only partially recovers vision in people with RP or other blindness disorders, this instance of success is an important milestone on the road to curing blindness. Better yet, there is hope for blind patients to recover their vision and see light once again. The success with AAV vectors in this treatment could impact future studies by validating the use of AAV vectors for delivery in treating other genetic disorders.