Gene therapy to help restore eyesight

DALLAS (AP) — When he was 9, Mason Two Crow learned he could be legally blind before he turned 18. A few years later, his doctors told him something else: Researchers were working on a treatment that could save his vision. But the therapy would have to arrive before Mason lost his eyesight.

The Dallas Morning News reports Two Crow, now 22, received an injection in July that he hopes will allow him to look through a microscope and fulfill his dream of becoming a doctor. For many years, his plans — including marrying his high school sweetheart and applying to graduate school — rested on the uncertain future of his eyesight.

The doctors who treated Two Crow are affiliated with the Retina Foundation of the Southwest, a nonprofit vision research institute in North Dallas. The doctors used a pioneering treatment known as gene therapy, which has the potential to fix mistakes in patients’ DNA. The first gene therapy was approved in August for childhood leukemia, and a second, for lymphoma, won approval in November.

Researchers have launched more than 400 gene therapy clinical trials, including the one for Two Crow’s condition, at U.S. medical centers. The trials help researchers determine if gene therapy is safe and effective against a range of life-threatening conditions including cancers, degenerative brain diseases, the bleeding disorder hemophilia and inherited immune deficiencies.

Doctors hope to eventually deploy gene therapy against a wider range of incurable disorders, ranging from peanut allergies to Parkinson’s disease.

“What you’re seeing is the tip of the iceberg,” said David Birch, scientific director of the Retina Foundation of the Southwest.

Treatments for eye diseases are among the furthest along in the medical pipeline. Luxturna, a gene therapy for another type of inherited blindness, is expected to be approved by the Food and Drug Administration by January.

The eyes make good gene-therapy targets for a number of reasons. Eyes are easy to access. Researchers have identified many of the gene mutations behind some of the most devastating eye diseases. And eyes are relatively isolated from the body’s immune system. In the late 1990s and early 2000s, an earlier gene therapy heyday, a patient died after suffering a severe allergic reaction to a form of the treatment. Four patients in other trials developed leukemia.

Since then, researchers have found safer ways of introducing new genes into patients’ bodies.

“It was a matter of going back to the laboratory and developing improved ways of doing things,” said Helen Heslop, director of the Baylor College of Medicine’s Center for Cell and Gene Therapy and president of the American Society of Gene & Cell Therapy.

Two Crow, who is a member of the Mandan, Hidatsa and Arikara Nation — also known as the Three Affiliated Tribes — grew up in Sachse, about 30 miles northeast of Dallas. He first noticed he was having trouble seeing in second grade.

He couldn’t make out the letters of the alphabet hanging by his teacher’s blackboard. He begged his parents for an eye exam and finally received one at a Walmart. By luck, the optometrist had just returned from a conference on rare diseases and diagnosed Two Crow on the spot.

He has a condition called X-Linked Retinoschisis, or XLRS, which is passed from mothers to sons and affects between 1 in 5,000 and 1 in 20,000 people.

Patients with XLRS lack a protein that helps maintain fluid balance in the retina, a group of cells at the back of the eye. As a result, fluid accumulates between the retina’s layers. The same protein, retinoschisin, also plays a role in transmitting signals from the eye to the brain. XLRS patients see a warped, blurry image that glasses can’t correct.

Two Crow was told to stay away from football and all contact sports, because an injury could further damage his eyes. If he roughhoused with his friends and cousins, his parents would yell at him to just sit still. He stood out in a community of teenagers who circled their schedules around sports.

Two Crow focused on his studies instead.

“It kind of molded me as a student,” said Two Crow, who has long, straight black hair. A pair of glasses are the only outward hint of his impaired vision. “I prided myself,” he said, “on the ability that I wanted to focus on academics.”

Four years ago, he traveled to the University of California, Berkeley as part of a study to better understand XLRS. There, he met with researchers and sat for a series of eye exams.

That moment marked another shift in his life: the decision to pursue science. He was struck by how casually the researchers dressed, how young they were and how well they related to him.

“I’ve never seen a researcher have, like, sandals and shorts and walk into a laser lab and just tell jokes,” he said. “I was like: ‘You’re so cool! I want to be just like you.’”

Two Crow enrolled at Oklahoma State University and majored in pre-medical studies. Two years ago, when he was a sophomore, he visited the Retina Foundation of the Southwest for a routine appointment. Lea Bennett, a postdoctoral fellow with a large eye tattooed on the top of her left foot, told him he’d been officially selected for the clinical trial.

“I knew it was on the table, but to be told it was going to happen was groundbreaking,” he said.

With a brighter future seemingly at hand, he married his fiancée, Lydia, whom he has known since elementary school.

For now, Two Crow is mostly independent despite his impaired vision. He drives and reads, though his eyes fatigue easily, which makes it difficult to study. When he has trouble making out cells under a microscope, his lab partner pitches in to help.

Lydia helps him navigate crowds and helps him recognize the faces of friends they run into. Those closest to him know not to yell, “Hey look at that!” — because he probably won’t be able to observe small or faraway objects.

In July, an eye surgeon collaborating with Birch’s team injected one of Two Crow’s eyes with the experimental drug. If the drug is FDA-approved, doctors will be able to inject the other eye. Manufactured by AGTC, a biotech company headquartered in Alachua, Florida, with offices in Cambridge, Massachusetts, the drug consists of healthy versions of Two Crow’s defective genes hidden inside a virus’s outer shell.

The virus delivers the healthy gene to Two Crow’s retinal cells, which should then begin manufacturing the missing protein. In animal studies, the gene and the protein helped close gaps in the retina and improved communication between the eyes and the brain.

But no one knows how much vision Two Crow and other patients will regain or for how long the benefits of the one-time treatment will last.

AGTC is still in the early stages of the trial. It has enrolled 18 volunteers out of a target of 27 at six sites, including the Retina Foundation of the Southwest, Massachusetts Eye and Ear and the University of California, San Francisco. At this stage, the company is studying safety and dose sizes. All trial participants have XLRS and receive gene therapy; the earliest volunteers had the poorest vision and received the lowest dose. As the trial has progressed, researchers have enrolled patients with better vision and given them slightly higher doses. AGTC will run a third phase, on a larger group of patients, to evaluate efficacy. Approval is at least three years away.

Meanwhile, the Two Crows are moving ahead with their lives. In May, Mason graduated from OSU and is applying to medical school.

They hope that this therapy, regardless of how much it helps Two Crow, will one day cure his 3-year-old nephew, their only other family member with XLRS. Perhaps he’ll have the chance to play sports his uncle never did.


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