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It has worked on mice and monkeys. And starting next month in Vancouver, scientists will begin a long-awaited trial to see if a new drug might also slow the progression of Huntington’s disease in humans.

The Centre for Huntington Disease at the University of British Columbia, led by neurologist Dr. Blair Leavitt, is already in the process of identifying six patient candidates who in August will participate in a trial for a drug known as ASO-HTT, the first drug to target the cause of HD: a mutant gene that produces a toxic protein.

The Vancouver trial group will be followed by other groups in Britain and Germany, bringing the total number of patients receiving ASO-HTT to 36. As well, there are a half-dozen other potential HD treatments in various stages of testing around the world, fuelled by a recent influx of millions of research dollars from a private charitable foundation.

No one is claiming ASO-HTT or the other proposed therapies are outright cures, but researchers are excited about the potential to reduce the debilitating impact of the disease. “I believe that we are going to find effective treatments, not just in my lifetime, but soon,” Leavitt says.

If ASO-HTT effectively slows the progression of HD, it might also be used to develop treatments for other neurological diseases such as Alzheimer’s, Parkinson’s and ALS.

But among those who have the most at stake, the news of a potential breakthrough treatment has been greeted with caution, even ambivalence.

“I don’t like to get hyped over things any more,” says Michelle, a 26-year-old in Ontario who tested positive for the gene four years ago. Michelle, who asked that her full name not be used, had watched the disease slowly kill her grandmother, and now her 58-year-old father struggles with it. “I also don’t like to put all my energy into that,” she says. “I don’t know what to think, to be honest.”

Dr. Blair Leavitt has been using mice in his research to find a cure for Huntington’s disease, but a new trial will test a drug on humans. (Rafal Gerszak for The Globe and Mail)

Huntington’s is genetic – its symptoms usually begin to show in a person’s early 40s, and then the disease takes about 15 to 25 years to destroy brain cells that control thought and physical movement. In later stages, it leaves the patient unable to talk, walk or swallow food. People with HD usually die from choking, infection or, oftentimes, a bad fall or accident due to problems with balance and co-ordination. Others who are bedridden and unable to communicate sometimes refuse tube feeding, not wanting to prolong the inevitable.

If a parent has Huntington’s, his or her children have a 50-per-cent chance of getting the genetic disease, too.

Not everybody at risk wants to be tested for the gene. It’s typical for families to deny the existence of HD and for those who are diagnosed to keep it a secret. And sometimes the disease simply goes unrecognized. If a family member shows symptoms when elderly, their tremors, lack of balance and confusion are usually attributed to old age. Other people can carry the gene but not get symptoms, passing it on to their children who can then develop the disease.

HD has touched my own life. My former partner has the disease. His father was the first to be diagnosed in his family. My ex’s brother also tested positive. They have a sister who does not want to be tested.

Like most people, I didn’t know anything about HD before meeting my ex. When his personality changed and he became apathetic, clumsy and prone to angry outbursts, I didn’t understand that the disease was the cause. He later told me that he worried each time he couldn’t remember something, or when he broke a glass. In his early 40s, when symptoms started interfering with his work, he finally got tested.

An HD diagnosis isn’t like a cancer diagnosis, where family and friends rally around. People don’t understand the personality changes that go along with HD, which can have profound effects on relationships. My experience as his advocate gave me some insight into the isolating aspects of the disease and how it can tear families apart. It’s a cruel genetic lottery – siblings who don’t test positive can suffer from guilt. The ones who do test positive need to find a way to live their lives without dwelling on what lies ahead.

'I believe that we are going to find effective treatments, not just in my lifetime, but soon,' Leavitt says.(Rafal Gerszak for The Globe and Mail)

Talk of testing the ASO-HTT drug on humans first emerged at the World Congress on Huntington’s Disease in Melbourne, Australia, in 2011, and has since generated a lot of excitement. “This could change everything for people living with this disease,” Bev Heim-Myers, chief executive officer of the Huntington Society of Canada, says.

And yet, those closest to the disease – people who have it built into their DNA – are more cautious. They have a lot more at stake if they get their hopes up. They feel safer living in the present with what they know.

Manny Abecia, 36, didn’t know HD was in his family until his mother was diagnosed in 2010. He remembers watching a TV show about the disease and realizing that his mother had the same symptoms. For his own testing, Abecia brought along his three best female friends for support. When the doctor told him he’d tested positive, they all cried. But he says it was also a huge relief: “It was like a ton of bricks off my shoulders, because I finally had clarity.”

Abecia would like to get married and have children, so he could easily be buoyed by the potential of a new wonder drug. But his reaction is more complicated, because clinging to hope can be exhausting.

“People have been hoping, for like, 20 years,” he says. “But it’s definitely grounds to be excited – especially because we’re seeing the top doctors in the world getting really excited. That’s something totally new.”

The gene that causes HD was identified in 1993, and in the past 10 years scientists have studied gene-silencing drugs from every angle, except the one that matters the most: how the drug interacts with the human brain. With this human trial launching in Vancouver, researchers get their chance.

The selected participants, who must all be showing early signs of HD, will receive ASO-HTT by intrathecal injection – a reverse spinal tap – to ensure it reaches the brain.

Manny Abecia tested positive for Huntington’s after realizing his mother displayed symptoms. ‘It was like a ton of bricks off my shoulders, because I finally had clarity,’ he says. (Jimmy Jeong for The Globe and Mail)

Leavitt’s team will watch the participants over the next six months. This first phase tests for safety and serious side effects. Second and third phases move into efficacy testing. A greater number of patients would be invited to participate as the trial goes along.

We all have two copies of the huntingtin gene, one each inherited from our mother and father, which play a crucial role in our brain development. When a gene carries the HD mutation, however, there’s a certain segment of DNA that goes wrong, repeating over and over, until it forms a dangerously long repeated sequence. If that CAG (cytosine, adenine and guanine) segment is repeated more than 40 times, the person will get Huntington’s disease. If it repeats between 35 to 39 times, they may or may not get it, or they might get it late in life. Or they might carry it and pass it along to their children, where the repeat could expand, causing their children to get the disease.

The problem is not only the mutant gene, but also the huntingtin protein created. The mutant DNA passes along instructions to a messenger, called ribonucleic acid (RNA). That RNA copy then produces a harmful protein that wreaks havoc in brain cells.

The ASO-HTT drug takes a “shoot the messenger” approach, entering cells and destroying the RNA so that the toxic huntingtin protein is not produced. Lab mice injected with the drug showed dramatic improvement in their HD symptoms. In humans, it’s estimated the drug will take about four to six weeks to take effect.

Because scientists know exactly what causes HD and who’s going to get it, researchers say it has an advantage over other neurological diseases in terms of finding a treatment or cure.

“It’s pretty simplistic compared to Alzheimer’s and Parkinson’s and ALS and other neurodegenerative diseases,” says Lisa Genova, the neuroscientist turned author, who recently released her new bestselling novel Inside the O’Briens, about a man who discovers he has HD and grapples with finding out if his four children have it, too. Genova previously wrote Still Alice, the bestseller about a woman with early onset Alzheimer’s, which was made into a movie. “So if we can figure out how to solve Huntington’s,” she adds, “what we learn may apply to the other diseases as well.”

There is another advantage that HD has over other diseases: the ultra-discreet billionaire Andrew Shechtel. (An investigative story by Bloomberg Press outed his astoundingly generous philanthropy last year, reportedly to his chagrin.) But the researchers all know him. Shechtel and his partners formed a non-profit research foundation called CHDI and have been funnelling more than $100-million a year into HD research.

Scientists in the field give CHDI a hefty share of the credit for the current flurry of research in HD. There are a total of five trials of varying drug therapies on humans under way this year, including the ASO-HTT trials in Vancouver and Europe (it is supported by CHDI, and is also a partnership between Isis Pharmaceuticals in California and the Swiss pharma giant Roche). In Israel, Dr. Michael Hayden, founder of UBC’s Centre for Huntington’s Disease, now heads up research at global pharmaceutical giant Teva, which is involved in two of the trials.

The drug being tested destroys RNA that produces a harmful protein. (Rafal Gerszak for The Globe and Mail)

***

Dr. Jeff Carroll is famous in the HD community because he is not only a researcher looking for a cure, but he is also gene-positive. Among six siblings, he’s one of four who have the gene, but no one is showing symptoms. Carroll is 37 and married with two children who do not have the gene, thanks to genetic screening and in-vitro fertilization.

On a tour of the Huntington’s research lab at Vancouver-based Centre for Molecular Medicine and Therapeutics, I was shown a pair of mice – a healthy, plump, muscular one and her slow-moving sister, an emaciated HD mouse with grey fur. The subject of spinal taps came up, which is how doctors can check for a build-up of mutant huntingtin gene in the nervous system. “Won’t that hurt?” I asked. “Oh, we’ve tapped Jeff,” a clinic staffer said, chuckling.

It’s true, he confirmed. He donated his cerebral spinal fluid for the cause.

“The only way to be part of it is to get behind the bus and push,” says Carroll, who worked at the UBC lab before joining Western Washington University in Bellingham, Wash.

Carroll, who has also received CHDI funding, doesn’t expect an overnight cure. He sees therapies unfolding incrementally, much the way HIV treatment has evolved so that few patients in Canada develop full-blown AIDS any more.

“I would love a magic bullet, but I don’t expect it,” he says. “It will be five years [of longer life] here, five more years there – and next thing you know, nobody dies any more, unless they don’t take their pills. You might be twitchy or loopy when you are 60 or 70 or something. There will be a push-back on the age of onset, but it won’t be obvious that it’s happening.”

Back in Vancouver, Leavitt – who’s been working on HD for 16 years – tells me the disease is often referred to as rare, but he thinks it’s far more common than it’s believed to be. About 14 people per 100,000 in Canada are affected, but for every person with the disease, it affects another five people. And there are still those who don’t know that it’s lurking in their families.

“If we can find a treatment that slows it down even by 50 per cent, that now pushes the age of onset to 75 – and that’s pretty darn good right there,” Leavitt says. “I don’t think that’s an unreasonable goal.”

As news of the UBC clinical trial has spread within the HD community, some patients have been eager to volunteer – Leavitt says he has received calls from as far away as Louisiana.

But there are strict criteria that must be met and one of them is living close to the clinic. As well, it’s a double-blind study, so a percentage of the participants will be receiving a placebo. Even Leavitt won’t know which patient is getting the actual drug.

“Clinical trials are massively expensive, and developing drugs for brain disease is really, really hard,” Leavitt says. “Less than 1 per cent of drugs developed for brain disease ever make it as an approved drug. So, the fact so many companies are interested and so many drugs are moving forward is an optimistic sign that we’re getting close to things that will work.

“My goal is to not work on HD – because it will be fixed,” he says, smiling. “And then I will go work on something else.”

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