With engineered proteins, scientists use optogenetics for the first time to help a blind patient see again

Somewhere in Paris, in a white room, seated at a white table, a man wearing a headset reminiscent of those worn by VR gamers reached out with his right hand and placed his fingers on a black notebook. This simple motion, which he executed with confidence, was notable for one very important reason: The man had been blind for close to four decades.

What was different now was that as part of a clinical trial, genes had been injected into one of his eyes, causing neurons in the retina to produce a light-sensing protein normally found in the slimy bodies of green algae. When the black goggles he was wearing projected video images of his surroundings as a pulsed light beam onto those now-light-sensitive cells, the neurons fired, and the signal traveled up the optic nerve and into the visual processing center of the brain. The genetically modified neurons had become stand-ins for the photoreceptors he had lost many years before to a genetic disease called retinitis pigmentosa.

The man’s progress identifying objects inside the lab and out in the world were reported Monday in Nature Medicine. While he couldn’t see colors or fine details, the case study describes the first time optogenetic therapy successfully restored partial vision to a blind patient.

“It’s a major milestone,” said study leader and ophthalmologist José-Alain Sahel of the University of Pittsburgh and the Sorbonne University in France.

He and his collaborators in Basel, Switzerland began experimenting with an optogenetics approach to treating retinitis pigmentosa in mice back in 2010. A few years later, they co-founded a company called GenSight Biologics to further develop the therapy and conduct clinical trials. They began recruiting patients to a Phase I safety trial in 2018, in Paris, London, and Pittsburgh, and the man described in this study was the first participant. “It was certainly the emergence of a lot of work over the last 13 years coming to light, but being able to be the first to demonstrate that optogenetic technology can work in humans is very exciting for us,” said Sahel.

Retinitis pigmentosa is a catchall term for a diverse group of progressive, hereditary diseases caused by mutations in dozens of different genes that cause the photoreceptor cells in the retina, known as rods and cones, to die off, leading eventually to total blindness. It afflicts more than 2 million people worldwide, and for most of them, there exists no cure.

Luxturna, the first gene therapy approved by the Food and Drug Administration for treating an eye disease, involves using a viral vector to deliver a working copy of the RPE65 gene. But less than 5% of retinitis pigmentosa patients carry that specific mutation. That leaves the majority of patients with only one option — an invasive microchip implanted onto the retina, which uses a glasses-mounted video camera to stimulate any photoreceptive cells still connected to the brain. Though approved in 2013, the device, named the Argus II, failed to restore more than a very pixelated version of reality, and as of 2019, only 350 patients worldwide had received the prosthesis.

“There’s not a lot of hope for people who get a diagnosis of retinitis pigmentosa today,” said Todd Durham, vice president of clinical and outcomes research at the Foundation Fighting Blindness, a patient advocacy organization. “When these folks lose the ability to see, they lose a lot of their independence and that brings with it a significant mental health burden. These are a very impactful set of conditions.”

Optogenetics is an important therapeutic approach because unlike implants and gene therapy it holds the potential to help people who’ve lost all function of their photoreceptors, said Durham. Invented in 2005, the technique involves inserting DNA into neurons to make them responsive to special light, and a way to shine that light onto them to turn them on and off. In lab mice, that often involves threading optical fibers directly into the rodents’ brains to study things like smell recognitionauditory processing, and addiction.

For this study, researchers injected one eye of a 58-year old patient with an adenovirus-associated vector carrying the genetic instructions for a protein called ChrimsonR. When amber light strikes it, the protein shape-shifts, allowing ions to flow in and out of cells. The vector targeted retinal ganglion cells, which in a healthy eye, would gather signals from cones and rods and shuttle that information up to the brain’s visual cortex. Even in patients with advanced retinitis pigmentosa, these ganglion cells are still alive, but left idling without any information coming in. The addition of ChrimsonR allows them to sense light themselves.

Sahel and his collaborators had previously tried a different protein, one that is activated by blue-green light. And in mice it worked great. But that end of the visual spectrum is very energetic, and when they moved to testing in primate models, they encountered problems.

In a normal mammalian retina, one photo-sensing protein would activate another and another and another, resulting in an cascade that amplifies the signal. One protein can open up to 1 million ion channels. With optogenetics, one protein equals one channel, so scientists need to amplify the signal another way — by adding more light. That’s what the goggles are for. But too much blue-green light can be toxic to the remaining cells (the reason why you shouldn’t stare directly into the sun). By switching to ChrimsonR and amber light, the researchers were able to strike the right balance between effectiveness and safety.

“It’s a small step forward but it is a definite step forward in that they’ve been able to prove that this does work in humans,” said Paul Bernstein, an ophthalmologist and retinal specialist at the University of Utah School of Medicine, who was not involved in the study.

The trial is a dose-escalation design, so the patient reported in the case study published Monday received the lowest dose, along with two other patients. He was the first to report some vision restoration in February 2020, right before Covid-19 ground the world to a standstill. The others who received the gene therapy treatment later were unable to return to the hospital for training with the goggles and lab testing. Sahel said they should be able to start that soon, as Covid-19 becomes less prevalent. Three additional patients have received the middle dose, and three more are expected to soon receive the highest dose.

In addition to the notebook, the first patient was able to locate and count other objects, like cups and a small bottle of light green liquid. The bigger the objects and the higher the contrast, the more consistently he was able to spot them. The patient also reported being able to see crosswalks outside on the street and even count the number of white stripes. During the lab-testing portion of the study, the researchers used an EEG to record the neuronal activity across the man’s visual cortex, which suggested that the ChrimsonR activation was indeed propagating up to the brain.

None of these changes were immediate. It took four to six months post-injection for the proteins to be expressed in sufficient quantities, and a few months of training with the goggles for the patient to be able to orient the beam of light directly onto those protein-expressing cells in the retina. To locate the objects, the patient used his whole head to scan the area back and forth. And the vision that was returned to him was a grainy world of black and white contrast. To do things like read or recognize faces would require much higher resolution than what the optogenetic approach could provide.

Still, for doctors like Bernstein, who have for decades had to tell most of their retinitis pigmentosa patients that there aren’t any good treatments available, it’s a welcome development. “The things that are happening now were just total science fiction when I started 26 years ago,” he said. He wants to see more data from the remaining patients in the trial. But the case study sends out an encouraging signal that individuals like this patient may one day be able to navigate a large part of the world that they haven’t been able to for a long time.

“These sorts of high tech approaches are bringing what was once a very distant horizon — restoring vision in these kinds of patients — much closer,” said Bernstein. “It’s really just amazing.”

In addition to GenSight’s study, there are currently two other clinical trials testing optogenetics for treating progressive diseases of the retina. The first started in 2015, is based on discoveries made by one of the unsung pioneers of optogenetics — Zhuo-Hua Pan of Wayne State University. The trial, now sponsored by Allergan, a unit of AbbVie, has reported safely dosing the first cohort of patients but hasn’t yet reported on the treatments’ impact on their sight. More recently, Bionic Sight, a company developing discoveries made by Sheila Nirenberg’s lab at Weill Medical College of Cornell University, began recruiting patients for its study, which also combines gene therapy with a set of biomimetic goggles.

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