Experimental gene therapy restores some vision in patients with inherited blindness

For her entire life, college student Olivia Cook had only a small degree of central vision. It was as if she was watching the world through a straw hole, and in dimly lit places, she could not make out people’s faces, only their silhouettes.

But after receiving an experimental gene-editing treatment to one of her eyes, she now can see things she never saw before.

Cook was born with an inherited retinal disorder that causes blindness, a rare type of eye disorder historically called Leber congenital amaurosis or LCA. A few years ago, she decided to participate in a clinical trial that involved using the gene-editing tool CRISPR to correct the form of inherited blindness that she has.

“My life has mostly changed in terms of being hopeful that there is going to be more science and findings in the future,” said Cook, 22, who is currently studying marketing and product development at Missouri State University in Springfield. She received the experimental gene-editing treatment through a surgery performed on her left eye.

“Now, post-surgery and post recovery, I am able to see in dimmer lighting with my left eye,” Cook said.

A treatment that used CRISPR was found to be safe and efficacious in improving vision among a small sample of patients with inherited blindness in the Phase 1/2 clinical trial that Cook participated in. Inherited retinal degenerations are a leading cause of blindness around the world.

Among a total of 14 volunteers, including Cook, the gene-editing tool was found to be associated with a “meaningful improvement” in vision for most patients around three months later and it was not directly tied to any serious side effects, according to the trial results, published Monday in the New England Journal of Medicine. The therapy remains experimental and the results need to be replicated in a larger group of people.

Months following the treatment, Cook was sitting with friends on a balcony that had Christmas lights wrapped around the railing. It was dusk, she recalled, yet she could see her friends’ faces glow under the twinkling Christmas lights. She was shocked.

“With my right eye, I was not able to see their facial features. I was only able to see their silhouette. With my left eye, I could see everything on their face – so, significant difference, especially in the dim lighting,” Cook said about that evening.

“One of the biggest ‘aha moments’ that I had was I had been talking to my mom one day after the surgery – it was about six to nine months after the surgery when I noticed most of my improvement,” Cook said.

“I could see a candle flickering behind me, which I’ve never seen that before,” she said. “I’d never picked up anything from over there before with the peripheral.”

Olivia Cook, 22, received the experimental CRISPR-based therapy and now says that her vision has improved. - Courtesy Olivia CookOlivia Cook, 22, received the experimental CRISPR-based therapy and now says that her vision has improved. - Courtesy Olivia Cook

Olivia Cook, 22, received the experimental CRISPR-based therapy and now says that her vision has improved. – Courtesy Olivia Cook

Before the treatment, Cook said that she sometimes could conceal the vision challenges she has had. Her limited vision often was an internal struggle.

“You wouldn’t really know that my eyesight is terrible until you spend a significant amount of time with me,” Cook said. “If we saw each other in the street, if I introduced myself to you, you’d never know.”

But now, she is no longer hiding.

A groundbreaking ‘proof of concept’

This study is the first time that CRISPR has been used in the eyes of living people.

“The results of this study provide proof of concept that CRISPR-Cas9 gene editing can be used safely and effectively to treat inherited retinal disorders,” said the study’s first author Dr. Eric Pierce, director of the Ocular Genomics Institute at Mass Eye and Ear and Harvard Medical School.

The trial was funded by the biotechnology company Editas Medicine and conducted in the United States by researchers at Mass Eye and Ear of the Mass General Brigham health care system and other US-based institutions, including the Perelman School of Medicine at the University of Pennsylvania, the University of Michigan, the University of Miami, and Oregon Health & Science University.

“We’re really hopeful that CRISPR-Cas9 gene editing technologies will now be applied to other genetic forms of inherited blindness, and indeed other genetic diseases in general,” Pierce said. “We’re hoping this will help open the era of therapeutic use of CRISPR-Cas9 technologies.”

The trial, which started in 2019, enrolled 12 adults, ages 17 to 63, and two children, ages 9 and 14, with inherited retinal degeneration caused by mutations in the CEP290 gene. That gene provides instructions for making a protein involved in many types of cells, including light receptor cells in the eyes. Mutations in CEP290 are the most common cause of severe early-onset retinal degeneration, which causes vision loss in children.

Currently, there is no treatment approved by the US Food and Drug Administration for CEP290-associated inherited retinal degeneration. These patients would not be able to read any lines of letters or numbers on a vision chart that most people receive at the eye doctor, and visual impairment may worsen over time.

For the trial, the 14 participants underwent a surgical procedure in which a drug called EDIT-101 that encodes the CRISPR gene-editing components was injected under the retina of one of their eyes. Since the trial was conducted to primarily evaluate safety and efficacy, only one eye in each patient was studied.

Dr. Jason Comander performs the surgical procedure to deliver experimental CRISPR-based medicine to a trial participant in September 2020. - Mass Eye and EarDr. Jason Comander performs the surgical procedure to deliver experimental CRISPR-based medicine to a trial participant in September 2020. - Mass Eye and Ear

Dr. Jason Comander performs the surgical procedure to deliver experimental CRISPR-based medicine to a trial participant in September 2020. – Mass Eye and Ear

“The subjects get an injection of the gene-editing drug, which is called EDIT-101, under their retina,” Pierce said. “That drug encodes the CRISPR-Cas9 gene-editing machinery, and once that starts working inside the retinal cells of those patients, it cuts out the mutation in CEP290 from the genome of their retinal cells, allowing the function of the CEP290 gene to be restored.”

When the first patients in the study were treated in 2020, it was the first time in medical history that a CRISPR-based medicine, resulting in gene-editing, was inserted directly into the living human body.

Among the adult volunteers, two were given a low dose of the medication, five were given an intermediate dose and five were given a high dose. Both of the children in the study were given the intermediate dose. The outpatient procedure took around an hour and a half.

The patients were then monitored every three months for a year and then less frequent monitoring continued for two years. In these follow-up visits, they underwent a series of vision tests among other evaluations.

The researchers found that 11 patients in the study had some type of improvement in their vision following the CRISPR therapy, and these improvements occurred about three months after the procedure and were sustained during subsequent visits.

Also, no serious side effects occurred in response to the treatment at any of the dose sizes, according to the researchers, and the adverse events that did occur were mild or moderate. There were also no signs that the CRISPR gene-editing caused ripple-effect harm to the genomes of the patients.

“The primary goal of this first in-human study was to test the safety of using CRISPR-Cas9 gene editing in vivo. When we started the trials, the subjects who were treated were the first patients ever to have received CRISPR-Cas9 gene-editing treatments in vivo,” Pierce said. “There were no serious adverse events related to the treatment, or the surgery required to deliver the treatment and no dose-limiting toxicities.”

Following the surgery, one patient experienced some bleeding in the eye, impairing their vision, but that has since resolved, according to the researchers.

“Once that hemorrhage cleared, the subject’s vision returned to baseline,” Pierce said.

Another patient experienced vision impairment associated with small mounds observed under their retina six months after the procedure. These types of hyperreflective mounds have been seen in other studies involving subretinal gene therapies, the researchers noted, and the cause of them is not clear.

“It’s thought to be inflammation,” Pierce said about the mounds.

The patient was treated with a course of steroid medicines, according to the study, and their recovery is ongoing.

“As the mounds resolved their vision also improved,” Pierce said. “I think this drug was as safe as possible in terms of design.”

‘It’s not a panacea’

Complete vision has not been restored among the patients. Most in the trial could not read any line of an eye chart prior to the study, and only four of them experienced some improvements in this ability. But some patients reported, after receiving treatment, being able to see their cell phones light up, differentiate various foods on their dinner plates, identify the spinning Apple icon on a computer screen or even noticing vibrant sunsets.

“I started to see what are described as bursts of color,” said Michael Kalberer, 46, who received the CRISPR treatment in his right eye and first noticed improvements in his vision about two to six months later. He started the study in 2020.

“It was a pretty cool moment to see strobe lights on the dance floor of my cousin’s wedding change color,” said Kalberer, who added that if he had not received the treatment, all he would have seen on the dance floor would have been shadows and flickering lights, and he would not have been able to identify the colors.

Trial participant Michael Kalberer at a follow-up appointment after receiving the experimental CRISPR-based therapy. - Mass Eye and EarTrial participant Michael Kalberer at a follow-up appointment after receiving the experimental CRISPR-based therapy. - Mass Eye and Ear

Trial participant Michael Kalberer at a follow-up appointment after receiving the experimental CRISPR-based therapy. – Mass Eye and Ear

Kalberer described the CRISPR treatment as “groundbreaking,” but warned it’s not a cure.

“It’s not a panacea,” said Kalberer, who still can’t see standard text or photos on a screen. “My disease is still here. It’s not gone. I’m not cured. … But it definitely slowed the progression of it.”

Pierce said that he hopes this approach to using CRISPR as a therapy for inherited blindness can be studied again in a larger and more diverse group of patients. All of the Phase 1/2 trial participants were non-Hispanic and White.

In 2022, Editas Medicine announced that it paused further studying CRISPR gene editing as a therapeutic approach for CEP290-associated inherited blindness and instead of conducting further trials, has continued to follow-up with the patients who have been treated to date.

The latest results from the Phase 1/2 trial support moving forward with a Phase 3 trial and then ultimately registering the therapy for possible FDA approval, Pierce said.

“We are working with Editas to identify an additional commercial partner for Phase 3 studies. We’re actually hoping this publication will stimulate interest in the biotech and pharma communities about that,” Pierce said.

More research over time could shed light on the long-term effects of the CRISPR-Cas9 gene editing tools, which, now that they have been injected into patients, will be present in patients for the rest of their lives, Pierce said.

“I think the real risk that we’re all concerned about with CRISPR-Cas9 gene editing is: Could the gene editing machinery that we’ve introduced into the retinal cells of these patients do something else, somewhere else in the genome, in addition to the therapeutic activities that it was designed for?” Pierce said.

“Could a cut in the genome be made 10 years from now, that could have an adverse effect over time? I think the answer to that is yes, it could. But we’re hopeful that risk is very low,” Pierce said. “That’s what we need additional follow-up for.”

‘Quality of life matters’

The results from the Phase 1/2 trial — and how patients experienced some improvements in vision — are a valuable reminder of how important quality of life can be for patients, said Art Caplan, a professor of bioethics and founding head of the Division of Medical Ethics at NYU Grossman School of Medicine’s Department of Population Health.

“Usually when we’re doing gene therapies or other innovative interventions, we associate them with saving lives. This experiment is a huge reminder that quality of life matters. This is about vision,” Caplan said. “No one’s dying. No one’s saved. But restoration of vision is an important achievement, and it’s a reminder that quality of life has to be factored into what we decide to cover in terms of insurance, reimbursement and what we try to study.”

He agreed with the researchers that more safety data over time would be helpful.

“They haven’t really had these subjects that long with the intervention to guarantee long-term safety,” Caplan said. “For these kinds of genetic interventions, you have to follow them over long periods of time — years — to make sure that other genes weren’t impacted.”

These new Phase 1/2 trial results provide a “building block” for scientists to work off of in the future when developing gene therapies to treat eye disorders, said Dr. Vlad Diaconita, a retinal surgeon and assistant professor of ophthalmology at Columbia University Vagelos College of Physicians and Surgeons. He was not involved in the trial.

“Does this apply to the American population at large? Not right now,” Diaconita said about the experimental treatment.

“It does, however, apply to the thousands of kids born in future years that have this particular genetic subtype. So yes, an approval of this particular gene delivery could benefit people over time,” he said. “It’s a proof of concept that seems to be moving us in the right direction.”

Diaconita’s colleague Dr. Aliaa Abdelhakim called this proof-of-concept study “groundbreaking” in the sense that it shows the treatment approach can be safe and result in some improvement for patients, but more research is needed on a larger scale to determine what kind of patients will benefit in the long term, and how long those improvements may last.

“We still have to wait a little longer to see if this pans out in the long-term,” said Abdelhakim, an ophthalmologist-geneticist, retina specialist and assistant professor of ophthalmology at Columbia University Vagelos College of Physicians and Surgeons. She also was not involved in the trial.

“We don’t know if improvements from this treatment are going to be sustained. Is their vision going to stay improved throughout their lives?” she asked. “The reason this is important is because this is the first time CRISPR has been used in this way, in the eye.”

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