Gene Therapy Is Successfully Treating a Common Form of Inherited Blindness

K.L. always knew he might be completely blind before reaching adulthood.

Even as a child he realized something was wrong with his eyes. Although he could see enough to navigate the world in daytime, as soon as the sun set so did his eyesight. Going out with friends was impossible at night. Eventually the world looked as if he was seeing through a large tunnel, focusing on only a tiny fraction at a time.

K.L’s condition didn’t have a cure. His family, and he himself, were well aware. “I was struggling deeply with what I thought my life would become,” he said, but then “my mum spotted the trial in a … newsletter.”

This month, K.L. became one of the first patients to receive a new experimental gene therapy for children with a severe form of inherited vision loss. The treatment, currently not yet named, targets young men who are susceptible to a particularly vicious genetic disorder that gradually destroys the light-sensing portion of their eyes.

Within a month following a single injection, “my vision was beginning to return in the treated eye. The sharpness and depth of colors I was slowly beginning to see were so clear and attractive,” said K.L.

The trial, a first-in-human case for X-linked Retinitis Pigmentosa (RP), was led by Dr. Robert MacLaren at the University of Oxford but spanned multiple centers including the Bascom Palmer Eye Institute in Miami, which previously championed Luxterna, the first FDA-approved gene therapy for a type of inherited blindness. The results are some of the first targeting a particularly difficult gene prone to mutation in humans. Amazingly, despite some inflammation in early stages, the therapy provided massive improvements in eyesight as early as two weeks following treatment.

Although primarily designed for safety and not to comprehensively study efficacy, the trail still offers hope to 1 in 4,000 people around the world battling gradual, unstoppable vision loss. But it also signals that gene therapy is rapidly coming of age for other neural degenerative problems—perhaps faster than previously anticipated.

“It is becoming more apparent to us that novel genetic therapies, when working, lead to a clear improvement in neuronal function, which holds great hope for a variety of other degenerative conditions that have a genetic basis,” said MacLaren.

X-Linked RP

K.L. is one of 80,000 or so people in the US with RP, a genetic condition that slowly eats away at the light-sensing portion of the eyes. RP can be due to one of tens of different mutations in genes that control how light receptors in the eyes develop. RP never had a treatment or a cure—the only option for people with the condition is to learn to navigate it without severely disrupting their lives.

In late 2017, everything changed. Luxturna, a gene therapy for inherited RP, was approved by the FDA. The treatment, a synthetic version of a healthy gene, was delivered directly into patients’ eyes—often young boys—to replace a faulty version that eats away at the back of their eyes, the retina.

The retina is a delicate, wispy sheet of tissue that contains elements sensitive to light. In RP, two light-sensing proteins in the retina begin dying out as early as infancy, wiping out a person’s peripheral vision and night vision. Most are legally, if not biologically, blind by their early 20s.

Luxturna came as a galvanizing shot to RP sufferers, yet it had severe limitations. A large portion of RP cases are caused by a particularly complex and volatile gene, dubbed RPGR, prone to mutations and other rearrangements. Even as a “miracle” cure, Luxturna could only tackle a small subset of patients with RP—about 1,000—that had a very specific mutation relying on Vitamin A chemical processing.

In other words, for K.L. and other RP suffers, Luxturna offered hope, but not relief.

Flexible Treatment

K.L.’s treatment took a direct stab at RPGR, which sits on the X chromosome.

Stay with me. We all know that biological females are generally dubbed “XX” and males “XY.” Biological females usually have two copies of the X chromosome, whereas males only have one copy.

This means that biological males are far more susceptible than females to contracting X-linked RP. If anything goes wrong with their single copy, unlike females, they don’t have a healthy “backup” to save the day. Unfortunately, the RPGR gene also happens to be quite temperamental and prone to genetic shifts that cause disease. It makes the gene a terrible test subject in the lab, where it tends to be unstable and difficult to work with.

After years of wrangling in animal models, however, the Oxford team was able to increase its “stability and fidelity,” so much so that when given to animal models with retinal disease, the stabilized, healthy version was able to restore visual properties.

In their first human trial, 18 patients with confirmed RPGR gene mutations and severe eyesight problems were separated into 6 groups, with each receiving a different dose of the therapy.

Similar to Luxturna, the healthy gene was packaged inside a virus carrier to deliver it into retinal cells in a simple injection surgery. To combat potential side effects of inflammation, which scientists previously found with similar treatments, the patients were given steroid pills to combat inflammation in the eyes.

Only one eye of each patient was treated in an effort to compare to the other, non-treated one. K.L., for example, opted to go for the one with poorer vision, thinking there was nothing to lose.

“The speed of my condition’s degeneration was unknown, so I had no choice but to apply and do whatever I could to hopefully help others in the future, as well as myself,” he said.

Promising Results

Although the three patients receiving low-dose treatment didn’t see notable results, others did.

Within a month, said K.L., “my visual field exploded and I could see so much more at once than ever before in that eye. Before long, the eye was undoubtedly better than the untreated eye.”

The improvements lasted at least six months, and only those who received the highest doses of the virus had minimal signs of inflammation, suggesting that the treatment is relatively safe.

Overall, seven patients gained back significant functionality in their eyes—not just night vision, as with Luxturna, but also their visual fields and clarity. What’s more, in some patients the outer regions of the retina also seemed to kick back into gear, regenerating their functionality even without direct treatment.

“We are delighted with the early results of this clinical trial for a degenerative eye disease,” said MacLaren. With X-linked RP, the goal is to slow or stop degeneration of the eyes, and despite somewhat inconsistent results between people, the therapy seems overall beneficial.

The results will next be validated in a broader population. Since performing the therapy, the Bascom Palmer team has further treated nine patients using the optimized dose determined from the trial, though outcomes have not yet been published.

For K.L., however, the trial has already revamped his life for the better.

“The results have been nothing short of astonishing and life changing for me, I really hope this trial is approved and they can treat what once was my better eye,” said K.L.

Image Credit: Free-Photos from Pixabay

Shelly Fan
Shelly Fan
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the co-founder of Vantastic Media, a media venture that explores science stories through text and video, and runs the award-winning blog Her first book, "Will AI Replace Us?" (Thames & Hudson) was published in 2019.
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