A new type of Gene Therapy demonstrates the potential to treat Blindness

(c) Veronique Juvin, Sciartwork

Doctors have been able to use a form of gene therapy described as optogenetics for the first time to restore partial vision in a blind person. The research team genetically altered retinal ganglion cells to become light-sensitive in a man whose vision was destroyed by retinitis pigmentosa, a genetic disorder that breaks down cells that absorb and convert light into brain signals.

A case study led by Prof. José-Alain Sahel of the University of Pittsburgh and Prof. Botond Roska of the University of Basel published in Nature Medicine provides the first detailed evidence in a peer-reviewed study of a person’s partial functional recovery of vision after optogenetic treatment.

The 58-year-old man described in the paper was the first patient in a clinical trial—partially funded by GenSight Biologics—designed to assess the safety and, secondarily, the efficacy of the therapy. Forty years before enrolling in the trial, he had been diagnosed with retinitis pigmentosa, a rare, genetic disease that results in the degeneration of the photoreceptor cells in the retina, leading to blindness.

Using special goggles, the patient went from total blindness to being able to detect a large notebook, a smaller staple box, glass tumblers and even the stripes of a street crosswalk, researchers reported in the journal.

"This is the first-ever patient that is reporting any kind of improvement through optogenetics," the gene therapy that made new cells light-sensitive, said lead researcher Prof. Jose-Alain Sahel, Chairman of Ophthalmology at the University of Pittsburgh.

Since its early days in the mid-2000s, optogenetics, with its potential to activate neurons with light, emerged as a promising technique for restoring vision in blind patients. In recent years, at least two companies have announced the start of clinical trials to test optogenetics-based therapies in humans.

Dr. Richard Rosen, chief of retinal services for the Mount Sinai Health System in New York City, and who was not part of this study, called the news "very, very exciting." And added: "This works for potentially the full gamut of patients who have these blinding diseases involving retinal damage".

The structure of the human retina is best described as inverted. Light-detecting photoreceptors are at the far back of the retina, while ganglion cells at the front transmit visual information from photoreceptors to the brain via the optic nerve.

The field of optogenetics involves the genetic alteration of cells so they produce light-sensitive proteins called channelrhodopsins.

To compensate for the loss of these photosensitive cells, the team sought to make existing retinal ganglion cells photosensitive, or respond to light, using optogenetics, thus bypassing the non-functioning layer of photoreceptors. In healthy conditions, the retinal ganglion cells receive information from photoreceptors via other intermediate cells.

Researchers injected into the man's eye a hollowed-out cold virus containing the genetic coding for a channelrhodopsin called ChrimsonR, originally derived from the algae Chlamydomonas noctigama, which is capable of sensing amber light.

The light-sensing protein, delivered via an adeno-associated viral vector, takes several months to be fully expressed on the surface of cells. Once this occurs, it needs to be activated with engineered goggles, which detect changes in light in the immediate surroundings and in real time project light pulses in the amber color spectrum—corresponding to the peak sensitivity of the inserted protein—onto the vector-treated retinal cells.

The coupling of the injection with the use of goggles is not enough to restore vision—the patient still required visual training to learn to control his eye movements and associate the visual perception of objects with their physical location. Before treatment, the patient could barely detect light, but after seven months of training, the patient began spontaneously reporting signs of visual improvement, Prof. Sahel said.

"The brain has to learn a new language coming from the retina, because what these ganglion cells are telling the brain are not the normal activity of the ganglion cells," said senior researcher Prof. Botond Roska, founding director of the Institute of Molecular and Clinical Ophthalmology Basel in Switzerland.

"Therefore, the retina is no longer blind," Prof. Roska said.

To rigorously assess the partial gain of vision, the team performed different tests in which the patient was asked to perceive, locate, count, and touch one, two, or three objects (a notebook, a staple box, or a group of tumblers) on a white table under different conditions. Without goggles, he could not carry out any of these activities at all, but when his injected eye was stimulated with the goggles, the success rate of his performance improved significantly—for instance, he could perceive, locate, and touch the notebook in 92 percent of the trials that involved the identification of this large object. 

The patient’s achievement in these trials was further confirmed by electroencephalography (EEG) that measure electrical activity in the brain. EEG showed that the man's brain was indeed responding to visual input from the eye and recorded distinct neuronal activity depending on the presence or absence of an object on the table.

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The gain of sight in this patient is limited and does not provide enough resolution to identify faces or read. This could be partially due to the low dose of viral vector the patient received. There were two other patients injected with the same dose.

Researchers cautioned that the man's vision is not expected to recover enough to be able to read or recognize faces.

"For recognizing a face, you need very high resolution. This is not yet possible using the approach we are using, so we should not give the hope to anyone at this point that they will be able to read or to recognize faces, because for that you need very high resolution," Prof. Roska said. 

But, as per Dr. Rosen, "the amount of vision the man has achieved would be incredibly important to the daily life of a blind person. These are people who are completely blind. There's nothing. They don't see anything. If they could detect large obstacles in their way, that's huge. Right now, they use a stick to tap around to see what's in their way. It's a small step, but it's also a huge step for these patients."

More people have been injected with this gene therapy, researchers said, but the COVID-19 pandemic hampered their ability to travel to medical centers where they could train with the special goggles.

"Because of COVID, only this patient was treated in time to be able to test the goggles and to be trained and to be brought back to the hospital and tested properly," Prof. Sahel said. The man hopes to receive more training and ultimately use his restored vision as much as possible throughout his daily life.

While excited by the report, Dr. Rosen urged cautious optimism until more research is done in more patients.

"It's one patient at this point," he said. "We don't know how well this is going to work with others, and it's something that's going to need refinement, but the proof of concept is really spectacular."

Source: 1, 2

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