Image: Alberta Health Network

Into the Dark

The first Canadian trials of an experimental treatment are aiming to cure a genetic disorder that causes blindness.

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Jul 15 2015, 7:17pm

Image: Alberta Health Network

Mo Rantucci is slowly, inevitably going blind. That fact is coded in his genes.

Rantucci is a 35-year-old office manager living in Alberta, Canada. He doesn't drive. He stopped when he was 30, and he told me that he thinks he should have gotten off the road even earlier than that. He bumps into things when a room is dimly lit or crowded with people. This is because Rantucci suffers from choroideremia, a rare genetic disorder that affects one in every 50-100,000 people—mostly men. His brother has it, too.

"They knew when I was 11 or 12," Rantucci told me, "but I wasn't officially diagnosed with blood tests until I was 19. I think they, meaning my parents, suspected earlier when they noticed I couldn't see very well."

Image courtesy of the Alberta Health Network

Choroideremia can first appear as poor nighttime vision among children, and as the affected person grows older, their sight only gets worse. The disease is the result of a gene mutation that prevents the production of a protein called REP-1 in the eye; without it, cells die prematurely. Everyone with choroideremia will develop blindness, and the disorder is incurable. The darkness will eventually come.

A bright spot appeared for Rantucci, however, when he learned about trials being planned at the Royal Alexandria hospital in Alberta for an experimental gene therapy treatment, which involves injecting a virus carrying new DNA—called a viral vector—into the eye so that it can be absorbed by the eye's cells and used to generate the correct protein, thereby curing choroideremia.

At least, that's the hope. After decades of work, gene therapy has yet to lead to a cure that's ready for mass consumption, although curing the incurable is the technique's raison d'etre.

"I'm hopeful, just as the patients are, but I don't have any data other than that it's safe"

In 2000, early gene therapy trials resulted in hundreds of cases where patients experienced "adverse events" after their surgeries, including death, which weren't reported by doctors. A more recent study found that after three years, the initial visual benefits apparently gained from gene therapy faded away.

Some recent successes have animated the current push for gene therapy trials, however. A 2014 gene therapy trial in the UK used the same viral vector as the Alberta trial, developed by a private UK company called NighstaRx, and found that out of the six patients that were operated on, two reported slight improvements in vision six months after the operation.

Rantucci told me he was aware of all of this and described himself as a "guinea pig." But when you're facing the slow and assured onset of blindness, and especially given the apparent success of the 2014 UK trial, it's "worth the risk," he said.

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On May 25th, 2015, Rantucci became the second person in Canada to undergo the gene therapy treatment for choroideremia. (The doctors only treated one eye, in case the trial ended in disaster.) The first patient, a 43-year-old Edmonton man named Ken Ross, had his operation just hours earlier.

A pipe with a tiny cutting instrument was inserted into Rantucci's eye, which sliced the microscopic fibers attaching the vitreous—the eye's clear jelly—to the retina so the jelly could be removed. The center of Rantucci's retina was blistered by the doctors, creating a puddle of fluid in the eye. The virus carrying the protein was then injected into the puddle. Overnight, his eye reabsorbed the liquid. Rantucci's brother had the same operation weeks later.

Although the operation is done, Rantucci's journey is just beginning. Regular checkups over the the following months and years will show whether the therapy actually resulted in improvements or not.

"I'm hopeful, just as the patients are, but I don't have any data other than that it's safe," said Ian MacDonald, the professor of ophthalmology at the University of Alberta leading the team behind the trials. "We're first showing that it's safe, and the other thing is showing that the eye doesn't lose vision over time. That's why we're following these patients over a number of years."

According to MacDonald, the Alberta study shows more promise than previous trials in part because it targets a different part of the eye. MacDonald's team targeted the central part of the retina in Rantucci and the other five patients, which is normally considered incredibly risky due to the damage that can occur.

The studies that failed in the past, MacDonald said, injected the viral vector into the peripheral retina. "It's really only the central retina that these patients have left," he explained. "The peripheral retina has already been lost due to degeneration; they only have the central retina."

"I would say the outlook isn't good if it doesn't work."

Less than two months after his surgery, Rantucci seemed reluctant to make definitive statements about his condition, but he did say that he's noticed improvements similar to those reported by patients in the 2014 UK trial. "I agree with what other people say—it seems brighter, things seem brighter compared to the eye that wasn't treated," Rantucci told me. "I'm told that I can see better, but from what I can tell things are just brighter, for sure."

Rantucci and the man who had his operation just before him, Ken Ross, regularly communicate about their condition, Rantucci said. He and his brother also keep close tabs on each other.

"I'm more so hopeful that they'll find that it's stopped the regression in one eye, and maybe they'll do the second eye," Rantucci said. "What happens if it doesn't stop it? Well, then I guess it would keep getting worse, and I'll keep losing vision. I'll just have to wait for the next study. There's always studies going on. But I'm hopeful it does, because I've seen people 10 years older than me, and they get around pretty bad. I would say the outlook isn't good if it doesn't work."

Image courtesy of the Alberta Health Network

According to MacDonald, a successful gene therapy trial in Alberta could open the doors to techniques that can successfully treat other degenerative disorders that affect the eye. "It's a bit futuristic, but there are many applications that people are actively interested in that would have an application to a broader population of patients," MacDonald said.

As cliché as it sounds, it's nonetheless true: time will be the ultimate judge as to whether the surgery performed on Rantucci, his brother, and four other Canadian men will result in a long term treatment for choroideremia or yet another disappointment for gene therapy. Both literally and figuratively, the patients and doctors involved in the trial at Alberta's Royal Alexandria hospital are heading into the dark.