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A gene-based therapy helped a blind man regain some vision

He can see objects thanks to light-activated proteins implanted in eye nerve cells and special eyewear.

A blind man has gained some vision thanks to a novel sort of gene therapy that rewires nerve cells in the eye.
The 58-year-old guy suffers from retinitis pigmentosa, a hereditary illness that causes light-gathering cells in the retina to die. The man could detect some light before receiving optogenetic therapy, but he couldn’t discern motion or distinguish objects.

Researchers report in Nature Medicine on May 24 that he can now see and count items, and that he has even reported seeing the white stripes of a pedestrian crosswalk. His eyesight remains limited, necessitating the use of special goggles that provide light pulses to the treated eye.

“It’s exciting. It’s really good to see it working and getting some definite responses from patients,” says David Birch, a retinal degeneration expert at the Retina Foundation of the Southwest in Dallas.

Birch has worked on various optogenetic medicines but was not involved in this study.
For more than a decade, researchers have been working on optogenetic therapy to help people with degenerative eye illnesses like retinitis pigmentosa regain their eyesight. When nerve cells are exposed to a specific wavelength of light, a light-sensitive protein causes them to send a signal to the brain.
Optogenetic therapy is not the same as standard gene therapy, which involves replacing a damaged gene with a healthy one. It’s also distinct from gene editing, which involves the use of molecular tools like CRISPR/Cas9 to correct disease-causing variations in specific genes.

The United States Food and Drug Administration (FDA) approved a conventional gene therapy in 2017 to cure inherited blindness caused by mutations in the RPE65 gene. Other researchers are doing clinical trials utilizing gene editing to fix a specific mutation that causes Leber congenital amaurosis 10, an inherited form of blindness.
According to Botond Roska, a neuroscientist and gene therapist at the Institute of Molecular and Clinical Ophthalmology Basel and the University of Basel in Switzerland, those therapies may halt or reduce the advancement of degenerative eye illnesses, but they don’t help patients who have already lost eyesight.

Although gene therapy and gene editing target specific genes, retinitis pigmentosa can be caused by mutations in any of more than 50 genes. Optogenetic therapy has the potential to aid patients who have lost their vision due to a variety of disorders, regardless of the gene mutations that cause them. Macular degeneration, which affects millions of individuals globally, is one of these disorders.
To make nerve cells respond to light, earlier versions of optogenetic therapy used a protein called channelrhodopsin-2 from algae. To function, that protein requires a lot of strong blue light. “It’s like staring at the sun in the desert,” says José-Alain Sahel, an ophthalmologist and retina specialist at the University of Pittsburgh and Sorbonne University in Paris.

The amount of light required to activate the protein could kill any remaining retinal cells. As a result, Sahel, Roska, and their colleagues devised a therapeutic based on a light-sensing protein that responds to amber light, which causes less cell damage than blue or green wavelengths.
The researchers utilized an adeno-associated virus to transmit the protein-making instructions to specific cells in the man’s eyes. The instructions were placed in a layer of nerve cells known as ganglion cells by the team.
The retina is made up of three layers: The rods and cones that gather light are located at the back of the retina. In the degenerative condition, those photoreceptor cells are the first to perish.

Bipolar cells are the next layer of nerve cells to appear. They interpret visual information and send signals to the third layer’s ganglion cells. The ganglion cells send messages to the brain’s visual regions.
Some researchers, including Sahel and Roska’s group, are also testing optogenetic proteins in bipolar cells, dormant cones (those that have lost function but haven’t perished), and other nerve cells. But, according to Roska, ganglion cells were the easiest to target. By injecting the virus into the center of the eye, they can be accessed. And ganglion cells survive the death of rods, cones, and bipolar cells.

Without special goggles that emit pulses of amber light to his eye, the Frenchman is still unable to see. Because ganglion cells normally respond to changes in light, this is the case. They won’t keep firing if the light is steady, thus pulses are required, according to Roska.
Furthermore, while normal vision can function in faint starlight to the brightest day on the beach, optogenetic proteins have a very narrow range of light levels in which they can function, according to Zhuo-Hua Pan, a vision neuroscientist at Wayne State University in Detroit who was not involved in the study. The goggles use digital camera technology to alter light levels automatically and broadcast them to the man’s eye.

According to Pan and Birch, those who receive optogenetic therapy may need to wear goggles to help interpret visual information before it reaches the brain.
The individual could see and distinguish objects such as a book, cups, and a bottle of hand sanitizer on a table thanks to the goggles sending pulses of light to his treated eye.
The researchers show that the individual needs the goggles in order to see the items.

According to Sheila Nirenberg, a neuroscientist at Weill Cornell Medicine in New York City and the founder of Bionic Sight, a business that is also utilizing optogenetics to treat blindness, the researchers would need to test if beaming the amber light into his eye before the therapy could be enough to allow him to see to prove the therapy worked. If that’s the case, the change in vision could be due to intense light alone, rather than the therapy itself.
In a March press release, her company stated that blind participants in a clinical experiment were able to sense light and motion after therapy. The findings are still preliminary. A full report from the clinical trial may be a year or more away, Nirenberg says.

In a November presentation at a virtual conference of the American Academy of Ophthalmology, Nanoscope Technologies of Bedford, Texas, reported it has also restored limited vision to some persons with retinitis pigmentosa. However, no comprehensive analysis of the data has been made public. “Without the details it’s difficult to evaluate,” says Pan.

Although Pan says he wants to know more about what the patient can see outside of the lab, the Nature Medicine paper is hopeful because it displays some of those features. Nonetheless, he expresses satisfaction that the efforts is now bearing fruit. “We’ve been waiting to hear this for many years.”

Sahel and Roska stress that the therapy is not a cure for blindness.  “For now, all we can say is that there is one patient … with a functional difference,” Roska says. Sahel adds, “it’s a milestone on the road to even better outcomes.”

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