Experimental gene therapy restores some vision in patients with inherited blindness


Throughout her life, student Olivia Cook had only a low degree of central vision. It was as if she was looking at the world through a straw hole, and in dimly lit places she couldn’t make out people’s faces, only their silhouettes.

But after receiving an experimental gene-editing treatment on one of her eyes, she can now see things she’s never seen 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 involving the use of the gene-editing tool CRISPR to correct the form of hereditary blindness she suffers from.

“My life has mostly changed with the hope that there will be more science and discoveries in the future,” said Cook, 22, who is currently studying marketing and product development at Michigan State University. Missouri in Springfield. She received the experimental gene-editing treatment through surgery performed on her left eye.

“Now, after surgery and after healing, I am able to see in dimmer light with my left eye,” Cook said.

A treatment using CRISPR was found to be safe and effective in improving vision in a small sample of patients with hereditary blindness in the phase 1/2 clinical trial in which Cook participated. Hereditary retinal degenerations are one of the leading causes of blindness worldwide.

Among a total of 14 volunteers, including Cook, the gene-editing tool was found to be associated with “significant improvement” in most patients’ vision about three months later and it was not directly linked to serious side effects, depending on the organization. results of the trial, 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 after treatment, Cook sat with friends on a balcony whose railing was surrounded by Christmas lights. It was dusk, she remembers, but she could see her friends’ faces glowing under the twinkling Christmas lights. She was shocked.

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

“One of the biggest ‘aha’ moments I experienced was I was talking to my mom a day after surgery. It was about six to nine months after surgery when I noticed the essential to my improvement,” Cook said.

“I could see a candle flickering behind me, which I had never seen before,” she said. “I’ve never picked up anything there before with the device.”

Courtesy of Olivia Cook

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

Before treatment, Cook said she could sometimes hide the vision problems she had. His limited vision was often the result of an internal struggle.

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

But now she is no longer hiding.

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

“The results of this study provide evidence that CRISPR-Cas9 gene editing can be used safely and effectively to treat inherited retinal disorders,” said study 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 biotechnology company Editas Medicine and conducted in the United States by researchers at Mass General Brigham’s Mass Eye and Ear Health System and other U.S.-based institutions, including the Perelman School of Medicine from the University of Pennsylvania, the University of Michigan, the University of Miami and Oregon Health and Science University.

“We really hope that CRISPR-Cas9 gene editing technologies will now be applied to other genetic forms of hereditary blindness, and even other genetic diseases in general,” Pierce said. “We hope this will help usher in the era of therapeutic use of CRISPR-Cas9 technologies.” »

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

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

For the trial, the 14 participants underwent surgery in which a drug called EDIT-101, encoding CRISPR gene-editing components, was injected under the retina of one of their eyes. Because the trial was conducted primarily to assess safety and effectiveness, only one eye of each patient was studied.

Eye and ear of mass

Dr. Jason Comander performs the surgery to administer an experimental CRISPR-based drug to a trial participant in September 2020.

“Subjects are injected with the gene-editing drug, called EDIT-101, under their retina,” Pierce said. “This drug encodes the CRISPR-Cas9 gene-editing machinery, and once it starts working inside these patients’ retinal cells, it removes the CEP290 mutation from the genome of their retinal cells, allowing thus the function of the CEP290 gene to be modified. restored. »

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

Of the adult volunteers, two received a low dose of the drug, five an intermediate dose and five a high dose. The two children in the study received the intermediate dose. The outpatient procedure lasted approximately one and a half hours.

Patients were then followed every three months for a year, then less frequent monitoring continued for two years. During these follow-up visits, they underwent a series of vision tests, among other assessments.

The researchers found that 11 patients in the study experienced some improvement in their vision following CRISPR therapy, and these improvements occurred approximately three months after the procedure and were maintained at subsequent visits.

Additionally, according to the researchers, no serious side effects occurred in response to the treatment, regardless of the dose, and the adverse events that occurred were mild or moderate. There was also no sign that CRISPR genetic editing had had a knock-on effect on patients’ genomes.

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

After the operation, one patient experienced bleeding in the eye, impairing his vision, but this has since resolved, according to the researchers.

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

Another patient experienced visual impairment associated with small mounds observed under the retina six months after the procedure. These types of hyperreflective mounds have been observed in other studies involving subretinal gene therapies, the researchers noted, and their cause is unclear.

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

The patient was treated…

News Source :
Gn Health

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