Crispr’s Quest to Slay Donegal Amy

A trial using the gene-editing tool inside the body hints at treating, or even curing, a rare fatal disease—and is changing a community in the process.

In the 5th century, in early medieval Ireland, Conall Gulban, an Irish king, gave his name to an area of land at the northwest tip of the Irish coast. His kingdom was called Tír Chonall, the “land of Conall”—or, today, Donegal. 

Somewhere along the king’s descendant line, known as Cenél Conaill or “kindred of Conall,” it’s thought that a mistake arose in a scion’s genome—specifically, a mutation of a gene responsible for producing a protein called transthyretin (TTR). The genetic error resulted in the birth of a rare condition known as hereditary transthyretin (ATTR) amyloidosis.

The TTR protein is made predominantly in the liver and is responsible for shuttling vitamin A and a hormone called thyroxine around the body. But in those with hereditary ATTR amyloidosis, the genetic mutation produces a botched version of it. This misshapen TTR aggregates and leaves clumps of amyloid, another protein, in tissues around the body—mostly the heart muscles and the nerves. These amyloid clumps interfere with tissues as they try to do their job, wreaking havoc. 

Today, along a 15-mile strip of the coast of Donegal, where the Irish language is still predominantly spoken in many areas, the mutation is found in about 1 percent of the population. The resulting disease—colloquially known as Donegal Amy—has ravaged Donegal natives for decades. 

It’s estimated that there are about 50,000 people with hereditary amyloidosis across the world, and Donegal Amy is just one type. It’s caused by a Thr60Ala mutation in the TRR gene, but there are more than 130 mutations of this gene that are thought to trigger other forms of the condition. Carriers of these mutations tend to crop up in hyperlocalized clusters. The most common mutation, Val30Met, first described in 1952, can be found in northern Portugal around the city of Porto, and has also been found in northern Sweden and Japan. Another, Val122Ile, primarily affects people of West African descent—about 4 percent of African Americans are estimated to carry it.

While each mutation produces a slightly different version of the disease, in the case of Donegal Amy, the condition typically makes itself known after the age of 60. It starts with a numbness in the body’s extremities, such as the hands and feet, and moves inwards as it progresses to causing tingling, unbearable pins and needles, and muscle weakness—all symptoms of polyneuropathy, or damage to the peripheral nerves. The disease quickly moves on to attack the autonomic nervous system, which regulates involuntary bodily processes, triggering weight loss, diarrhea, constipation, and urinary incontinence. The polyneuropathy is also accompanied by cardiomyopathy, a disease of the heart muscle where the heart isn’t able to pump blood as easily, causing breathlessness, chest pain, and swelling of the legs, ankles, and feet. Patients die between three and 15 years after diagnosis, usually due to chronic heart failure. 

Because the symptoms of hereditary amyloidosis are so heterogeneous, doctors rarely know when they’ve got a case on their hands. A patient wouldn’t usually tell their heart doctor about their carpal tunnel syndrome, nor would their neurologist know to scan for a heart block. “The entire diagnostic pathway is riddled with pitfalls,” researchers have noted.

“It’s a truly awful disease,” says Julian Gillmore, head of the National Amyloidosis Centre at University College London, who has been at the heart of efforts to develop treatments for it. It doesn’t just take away a person’s health; it erodes their ability to work, to socialize, to leave the house. The disease is progressive, devastating, and always fatal. 

THE FIRST FEW cases of Donegal Amy were reported in the Canadian Journal of Neurological Sciences in 1983. The authors conjectured that there might be a hereditary element to the disease, based on the fact that some of the patients had reported relatives suffering from a similar condition as well as their oddly close geography. In 1987, a further seven cases in seven families in Donegal were documented. 

The same year, a similar condition was reported in a family in the Appalachian region of the United States. Researchers identified the genetic fault causing it as a Thr60Ala mutation to the TTR gene. In 1991, a genetic analysis in two more patients from Donegal isolated the same genetic variant. As the ancestors of the Appalachian family had emigrated to West Virginia in the early 1800s from Derry in Northern Ireland, which borders Donegal to the east, scientists hypothesized the families shared a common ancestor. When the Irish diaspora drifted across the world in the 19th and 20th centuries—forced to leave by the Great Famine or a lack of jobs—the genetic mutation seemingly drifted along with them.

The mutation was also initially suspected to have drifted into Ireland too. The authors of the 1987 paper on the Donegal cases speculated that hereditary amyloidosis had been brought to Donegal in the 16th century by Portuguese sailors with the Spanish Armada, many of whom ended up shipwrecked on the coast of northwest Ireland on their return home after a punishing defeat by the English. The first case of hereditary ATTR amyloidosis was documented in 1952 in Portugal, so the researchers reasoned it had begun there (though cases there are in fact driven by Val30Met rather than Thr60Ala mutations). But further analysis uncovered that six of the seven Irish families originally found to have the condition shared a common ancestral surname, with the original family with this surname descending from Donegal’s namesake—Conall Gulban. 

The disease was also initially believed to be rare—ultra-rare even. But as methods for diagnosis have become more sophisticated, it has proven to be far more common than once thought. In 1999, Gillmore’s unit had about 150 referrals a year; today, it gets 3,000. The most commonly missed version of the condition is wild-type ATTR amyloidosis, which arises sporadically—it’s thought to affect between 200,000 and 500,000 people worldwide. Hereditary ATTR amyloidosis, on the other hand, is an autosomal dominant inherited condition, meaning that carriers have a 50-50 chance of passing the mutated gene on to offspring. Not all carriers of a mutated gene will go on to develop the disease, and the likelihood of doing so varies according to specific mutation carried.

GILLMORE ENTERED the amyloidosis field on a fluke. As a medical student, he applied for a research job in immunological medicine. He flubbed the interview so badly that his interviewers told him so to his face immediately afterwards—but he was the only applicant, so he got the job. He worked under one of his interviewers, Philip Hawkins, who became head of the National Amyloidosis Centre in the United Kingdom, the role that Gillmore now holds. 

Back then, when he was starting out seeing patients, the disease was, in effect, a death sentence. “It was such a depressing clinic,” he says. All they could offer patients was symptom management: stronger painkillers for nerve pain or medication for their diarrhea. Liver transplants helped a little, but it could only be done early in the course of the disease, and it didn’t help those whose condition affected their heart.  

So when Rosaline Callaghan, whose family hails from the Inishowen peninsula in the north of Donegal, learned in 2007 that she carried the gene, she had no inclination to suffer the devastation of the disease. She knew the likelihood was high: Her aunt—one of the case studies in the 1987 paper—had died from the same condition in 1982, and she had watched her father die slowly from it over the course of seven years, finally passing away at 67 after 22 months in a hospice. She was told it was highly unlikely that she would see a treatment in her lifetime. Eight years later, she quit her job as a barrister, sold her house, and went traveling. “If I’m lying in bed for months, I’m gonna regret not doing this,” she thought. The disease’s harbinger finally arrived in October 2018; she lost feeling in the soles of her feet. She was diagnosed in 2019. She reached out to a friend who agreed to help her get to Switzerland, where assisted dying is legal, when the time came. “I had an exit strategy in place.”

But in the time between Rosaline learning she carried the gene and being diagnosed with the condition, the ongoing genomic revolution had borne fruits in the form of genetic treatments for ATTR amyloidosis. Gene silencers, such as a drug called patisiran, choke off the production of TTR in the liver, including the abnormal kind. Patisiran became available in Northern Ireland in 2019, and after much protest and lobbying, in the Republic of Ireland in October 2021. In June 2019, Rosaline received her first infusion, and about nine months later, she awoke one morning and her nerve pain levels—previously near unbearable—had plummeted down the pain scale. With her condition now treatable and euthanasia no longer her only option, she says she feels she can do whatever she wants, because it’s all just on extra time. “I can decide to go horseback riding in the fucking nude on the beach,” she says. “I just need to find somebody who will lend me a horse.” 

But while these drugs have been shown to slow disease progression or even reverse it long-term, they require continuous administration—lengthy infusion processes every three weeks in the case of patisiran—and can have serious side effects. 

Enter Crispr. Gillmore is the lead investigator of the first ever gene-editing clinical trial in human patients with ATTR amyloidosis—and it is one of the first times Crispr has been used to edit a gene directly inside the body. The trial is not only to demonstrate that gene editing can be safe, but that it can potentially cure devastating diseases by simply correcting a typo. 

Paddy Doherty, who has strong roots in Gweedore in County Donegal, was the fifth person in the trial to receive the infusion. Paddy’s own father died from the condition in his sixties, although at the time it was put down to angina. It wasn’t until a cousin living in England got in touch and asked to come over and talk to the family that Paddy learned that it was more likely his father died from something he had never heard of—ATTR amyloidosis. The cousin had been diagnosed with the same condition and died within the same year; his sister urged Paddy to get checked for the gene.

But Paddy felt healthy. In his early sixties, he was an avid walker, hiking the Camino de Santiago pilgrimage in Europe and trekking the Himalayas. However, in the autumn of 2020, while walking his dog, a steep hill that previously posed no problem left him breathless. At the urging of his wife, he visited the local hospital and was diagnosed with ATTR amyloidosis. In early 2021, Paddy traveled to London and was screened for the Crispr trial by Gillmore. In April of that year, he received an infusion of the treatment in a London hospital. 

The drug, called NTLA-2001, works by inactivating the TTR gene and stopping the genetic expression of TTR in liver cells. It contains a protein that functions as a pair of molecular scissors, as well as an RNA molecule, analogous to a GPS, that guides the scissors to the faulty gene. When the scissors arrive they cut into the gene, turning it off and stopping the production of the TTR protein. 

All six patients in the trial, which included Paddy, had hereditary ATTR amyloidosis, with polyneuropathy as their major suite of symptoms. The results were reported in The New England Journal of Medicine in June 2021. While the trial was just a Phase I, which primarily just tests for safety, it was found to lower levels of TTR by an astonishing 90 percent after 28 days. And this reduction was found to last four to six months after the initial injection. “It’s a real milestone for modern medicine,” says Kiran Musunuru, a professor of medicine at the University of Pennsylvania Perelman School of Medicine and author of The CRISPR Generation. “It impressed everyone in the field—it just seemed like a home run.”

Gillmore’s unit had already established the basic paradigm behind the Crispr trial: that if you knock down the TTR gene, then this quells amyloid build-up—halting and even reversing the disease—and data on the gene-silencing drug patisiran has suggested this to be true. The goal with the Crispr treatment is to reach a point where existing amyloid deposits are cleared at a quicker rate than new amyloid is being deposited, which is when Gillmore suspects significant improvements will reveal themselves. But this will likely take a few years to show—although Paddy says he already feels improvements in his health. He recently had his 18-month followup, and his TTR levels had stayed reduced by about 96 percent, one of the most dramatic reductions in the trial. The study has since been expanded to include a further 12 patients with cardiomyopathy. 

“It is the one trial that has by far shown the most success so far,” says Musunuru. Ultimately, it could extend the lives of these patients by a few years, which, at first blush, may not sound like a big deal, he says. “But, you know, when you’ve been diagnosed and only have a few years left to live—because the diagnosis is so grim—being able to double that time, that’s actually such a big deal.” 

One concern that accompanies all Crispr treatments is the possibility of off-target editing—where Crispr’s molecular scissors cut into an unintended gene, with the capacity to trigger something like cancer. “I think we have to acknowledge that that is a potential risk,” says Gillmore. So far, animal studies with the drug have yet to show any off-target editing. The other big issue is the eventual cost: genetic treatments are likely to be astronomically pricey when they become fully available. 

Nevertheless, the trial marks the first time it’s been shown to be safe to edit the genomes of cells in the body. “It’s not just about transthyretin amyloidosis,” says Musunuru. “This is just the beginning—this is going to transform the way we practice medicine.” 

For decades, Donegal Amy was an illness shrouded in secrecy, a familial problem kept behind closed doors. “There was a common theme running through, which was that the people who had it didn’t speak about it, because there was no cure,” says Paddy. Instead, sufferers were said, in hushed tones, to have “took to the bed.” In a densely Catholic area, many believed it was God’s will—that they had been served the hand of God, and they should not fly in the face of it. 

That’s all changed now. Families previously afraid to admit to carrying the disease have begun to emerge from the woodwork, ready to receive the treatments that science is becoming able to impart. “I just feel so, so privileged to have been part of this revolution,” says Gillmore.

Crispr’s Quest to Slay Donegal Amy

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