In the early stages, a person suffering from Huntington’s disease (HD) might not seem so different from anyone else having a pretty bad day. Early symptoms include clumsiness, irritability, depression, and mood swings. An affected person might fidget a lot or get into car accidents. In many cases, people diagnosed with HD or their family members look back and realize it was probably the disease that ended their marriages or made it impossible to keep their jobs.
It’s later that the uncontrolled movements known as chorea — considered the hallmark symptom of HD — set in. “Chorea” is derived from the Greek word for “dance,” as in “choreography,” and is used to describe the constant, uncontrollable motion — the unpredictable jerking and twitching — that plagues many HD sufferers. Upon seeing a person with HD, many people who don’t know any better assume they’ve got a drinking problem or cerebral palsy.
Kristen Powers, who, from the age of 9, watched her mother fade away from Huntington’s, explains that if you were to come up with a grab bag of symptoms characteristic of Parkinson’s, Alzheimer’s, bipolar disorder, and ALS (Lou Gehrig’s disease), “you’d get a different version of Huntington’s each time.” There are treatments to help ease some of the symptoms, but so far there’s no cure and no way to slow the progression of the disease.
“No one has survived HD,” says Jeffrey Carroll, an HD researcher at Western Washington University in Bellingham. “No one in history.”
Most people with HD don’t live more than 10 to 20 years past the onset of clear symptoms. The degenerative disease is unforgiving in other ways, too, striking people while they’re still in the prime of their lives, with a typical onset of diagnosable symptoms developing by around age 40. HD is an inherited disease, but, unlike many genetic disorders, it takes only one genetic hit to make the eventual diagnosis of HD a certainty, assuming a person lives long enough. Many people who know that the emergence of HD symptoms is only a matter of time contemplate suicide, and about one in four attempt it. Any child born to a person with HD has a fifty-fifty chance of developing the disease.
Even those lucky enough to dodge that genetic bullet often face a future burdened by the disease. HD family members frequently act as caregivers for a brother, sister, or parent with the condition. As a result, in addition to HD’s easily misunderstood symptoms, a thick cloud of stigma, shame, and fear has followed people suffering with HD and their entire families around for generations. It’s a struggle that, historically, has not been handled well.
“Huntington’s was really the canonical condition where you would lock up your own mother in a mental asylum rather than talk about it openly — not just with friends and acquaintances, but with members of your own family,” says Ed Wild, a neurologist and HD researcher at University College London. “People would commit their first-degree relatives to mental asylums so that word would not get out, even within the family, that this horrendous genetic threat was ripe in the family and could threaten marriageability prospects. It’s a real horror story of self-perpetuating shame and stigma, where it wasn’t talked about. And then, because it wasn’t talked about, when it eventually reared its head, as it always does, it was all the more difficult to deal with.”
Thankfully, HD is rare in the general population. It is said to affect about five people of European descent per 100,000, with lower rates in some parts of the world. It’s more recently become clear that, rare as it may be, the prevalence of HD has likely been grossly underestimated as families hid their affected relatives. There are stories of people begging not to have HD listed in their medical records or, later, on death certificates. A recent estimate suggests that as many as one in 2,500 people may carry the mutation that leads to HD. Another one in 400 fall into a genetic gray area and may also be at risk.
It’s hard to overstate just how difficult it’s been for many HD families. People suffering from the condition have sometimes been suspected of dark magic and supernatural powers. An annotation published in the medical journal The Lancet in 1933 notes that, “Of all diseases likely to procure for the victim a reputation of sorcery, Huntington’s chorea was surely the most apt. What could be more natural than to attribute its strange, purposeless movements to the antics of a familiar spirit in the body? As the malady progressed the supposed witch became more and more ill-tempered and malicious, making enemies of all her neighbours, until she established herself inevitably as the first suspect at the next witch-hunt.”
Catching the Culprit
A diagnosis of HD was and is a frightening prospect to be sure, but of course it has nothing to do with witchcraft or sorcery. As complex neurodegenerative disorders go, the genetic cause for HD is surprisingly straightforward: People who carry a single, overly long copy of the gene known as huntingtin (HTT), usually passed down to them from one parent or the other, will go on to develop HD. About 3 to 5 percent of people with HD are the first in the family to have the genetic abnormality and have no family history of the disease.
HD was among the first inherited neurodegenerative disorders whose genetic cause was understood. By 1983, researchers led by Nancy Wexler, a neuropsychologist at Columbia University, were already hot on the trail of the mutant version of the Huntington’s disease gene. Wexler’s interest in HD was personal. She learned from her father at the age of 22 that her mother, Leonore, had the disease, as did many of her extended family members. That meant she and her sister were at risk. (In HD research the lines between HD expert and patient or family member often blur. Carroll, too, comes from an HD family and, based on his genetic test results, is destined to succumb to its symptoms unless a treatment comes along soon enough.)
The breakthrough discovery of a DNA marker for HD on chromosome 4 was made possible thanks to the participation of villagers in the Maracaibo region of Venezuela, which has the highest concentration of HD anywhere in the world. In some areas in and around Maracaibo, the rate of Huntington’s is said to be as high as one in 10. The leap to find the specific disease gene would be a trivial exercise today, but at the time — well before the Human Genome Project — it was a major undertaking. It would take another 10 years to narrow the cause of HD down from that DNA marker to the mutant form of HTT. Although the pace was slow by today’s standards, the discovery was a major victory. The HD gene was among the first disease genes ever to be cloned.
As Wexler has said, the discovery “absolutely changed the planet.” For HD families, it surely did. Suddenly, people at risk for HD weren’t stuck waiting around for symptoms to set in, wondering whether each time they tripped or dropped something was the beginning of the end. If they chose to, they could be tested to learn in advance, and usually without question, what their fate would be. In reality, most people at risk of HD today still aren’t tested before symptoms appear for a variety of reasons. (See “Why Aren’t More At-Risk People Tested for HD?” page 50.)
The discovery also made it possible to tackle HD’s biology in ways not possible before. It was suddenly feasible to develop and study mice with HD and to begin to think about ways the disease, as opposed to just its symptoms, might be targeted and treated. Hundreds of research papers have since been published in the scientific and medical literature describing various aspects of the disease. And yet, nearly 25 years after the HD gene was discovered, there’s still no cure, nor any way to slow disease progression.
“We are really lucky,” Carroll says. “We were one of the first genetic disease communities to have the underlying mutation mapped. We were among the first people to know that this bit of DNA causes the disease and to be able to test for that.”
But, he says, in many cases, people with other conditions who got their genetic answer more recently have more effective interventions than HD sufferers do. It’s not for lack of trying. “Unfortunately,” he says, when researchers found the gene, “they found a really big, really weird gene.” HTT can be up to six times longer than the average gene. Much about the HTT gene and the protein it encodes, he says, is still “super mysterious.”
The HTT gene’s DNA sequence includes a series of CAG repeats near its start — CAGCAGCAGCAG and so on. In healthy people, the gene usually includes about 17 such repeats. The mutant gene, on the other hand, has 36 or more CAG repeats. If a person has 40 or more CAGs in their HTT gene, they will, with certainty, develop Huntington’s. People with 36 to 39 CAG repeats can develop HD, but not necessarily within a normal lifespan. Generally speaking, the more repeats a person has, the sooner symptoms will set in.
Despite decades of study, researchers are still getting a handle on the function of normal HTT protein. The U.S. National Library of Medicine’s Genetics Home Reference entry on HTT says, “The HTT gene provides instructions for making a protein called huntingtin. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain and is essential for normal development before birth. Huntingtin is found in many of the body’s tissues, with the highest levels of activity in the brain. Within cells, this protein may be involved in chemical signaling, transporting materials, attaching (binding) to proteins and other structures, and protecting the cell from self-destruction (apoptosis).” It has also been found to play a role in cellular survival, movement, recycling of waste materials, and regulating the extent to which other genes are turned on or off.
In other words, it’s complicated — HTT appears to be almost everywhere, doing all sorts of different things. “If you ask 10 HD scientists what the HD protein does, you’ll get a different answer from each of them,” Carroll says. Adding to the uncertainty is the fact that laboratory knockout mice, in which researchers have inactivated the HTT gene in genetically altered embryos, die before they’re ever born; thus, it isn’t possible to study them in search of clues to HTT’s usual function.
When it comes to the mutant version of the gene, the biology is clearer, if not complete: The mutant HTT gene produces abnormally shaped HTT protein. That overgrown protein accumulates in the brain, like piles of garbage that the cells’ waste removal systems ultimately can’t handle. Eventually, all that accumulated junk leads to the malfunction and death of neurons in brain areas critical to movement, personality, and behavior.
The Great Hope
The challenges in studying HTT and in tackling a brain disorder in general led to what Carroll calls a “long, depressing lull” in definitive progress following the successful gene mapping. These days, however, things are finally starting to look up. Scientists are making progress on dozens of new HD treatments. Stem cell therapies and gene-editing tools, like CRISPR, hold promise. Recently, researchers at Emory University used CRISPR to edit out part of the gene that produces the mutant HTT protein in mice engineered with Huntington’s. The scientists discovered that, although the mice still had impaired movement, their ability to move improved and that the HTT protein had almost disappeared from the brain weeks later.
But perhaps the best hope among treatment strategies for now — the one that has everyone in the HD community waiting with bated breath — is an approach known as gene silencing. The concept seems simple enough: tell cells to stop making the faulty HTT protein from the template of the mutant gene. The strategy has the advantage of tackling the disease right at the root of the problem. It also sidesteps the need to understand all the ways in which mutant HTT is toxic and ultimately deadly.
“It doesn’t matter if we know what [the mutant protein] does,” Carroll says. “Turning off the gene, in theory, is the perfect way to fix it.”
There’s incontrovertible evidence, says Sarah Tabrizi, a neurologist and neuroscientist who is Wild’s colleague at University College London, that the mutant HTT produces a toxic protein. “Without mutant HTT, you don’t get HD,” she says. That’s been shown very clearly in mice. Treatment of animals carrying a mutant HTT gene with drugs designed to interfere with the protein’s production in the brain protects the animals from HTT accumulation and HD symptoms.
“If you target DNA and RNA, it doesn’t matter what the pathogenic pathways are,” Tabrizi says. “That’s where the great hope is.”
But will it work in humans? The answer isn’t yet known, but it will be soon. In 2015, Ionis Pharmaceuticals (formerly known as Isis Pharmaceuticals) launched an early-phase safety trial of a drug now dubbed IONIS-HTTRx, an antisense oligonucleotide (ASO) designed to target the HTT gene to reduce the amount of HTT protein produced. Participants diagnosed with early-stage HD receive four monthly injections of the experimental drug into the cerebrospinal fluid around the spinal cord, where it travels to neurons in the brain that are at risk of damage.
So far, the safety profile in trial patients is encouraging. That’s especially good news, because IONIS-HTTRx isn’t selective; the drug targets total HTT, meaning both mutant and non-mutant forms of the protein. Since the role of non-mutant HTT in an adult brain is not understood, it’s impossible to know for sure whether lowering it will be tolerated. However, Ionis tested IONIS-HTTRx exhaustively in animals prior to beginning the human trial, including looking specifically for any adverse effects of lowering non-mutant HTT, and those tests supported advancing to human trials.
The researchers have managed the potential risk of adverse reactions by increasing the dose gradually, with careful monitoring. They also note that the ASO-based drug has the advantage of being fully reversible and can be dosed at different levels to give a reduction in mutant and non-mutant HTT that provides the best efficacy and safety profile.
Now two years in, there’ve been no unpleasant surprises. As safety trials go, that’s about as good as it gets. In fact, in late June Ionis announced that patients who completed the trial would be eligible to participate in an open-label extension study, in which all participants would receive the drug. By the end of the year, or perhaps early next year, results of the trial should be in. If safety endpoints are met, a phase 3 trial to test whether the treatment offers HD patients any benefit will be the next step.
“We’ve come a really long way,” Wild says. “It’s very difficult for me to express it in a way that conveys the genuine, paradigm-shift type of feeling I have about this, but this is really an incredible time in HD [research]. There are people in the world who have doses of a drug designed to lower huntingtin in their nervous systems that is targeting the known cause of pathology in Huntington’s disease. And that’s never happened before.”
Wild says he’s also encouraged by the FDA’s recent approval of a similar drug called Spinraza (nusinersen) for treating another devastating inherited condition called spinal muscular atrophy. (See “Major Milestone,” page 32, in Genome’s Summer 2017 issue.) It’s evidence that antisense drugs can be successful in treating devastating neurological disorders. There’s finally real hope for treatments tackling HD, and it’s not just IONIS-HTTRx. Several companies are now working on various drug alternatives designed to target mutant HTT in slightly different, and in some cases, even more selective ways. There are other novel drugs and strategies making their way through the drug development pipeline, too.
The stigma of HD also seems to be eroding as social media has catalyzed connections among people, younger generations especially, facing similar struggles. Instead of hiding away alone, it’s suddenly easy to find other people who can relate and share stories. Organizations like Huntington’s Disease Youth Organization (HDYO), a nonprofit dedicated to young people affected by HD, and HDBuzz, an internet portal for sharing information about the disease founded by Carroll and Wild, have helped to lead the way.
“As long as you know you’re at risk of HD, you’re going to Google it,” Wild says. “Before you know it, everyone in the world who’s affected by HD or impacted by it is connecting with everyone else in the world … The current generation growing up with HD has a completely different attitude. Rather than hiding it, their instinct is to publish and share adverse news, and then they receive an inpouring of help from people in similar situations. It’s a 180-degree reversal in the way people deal with this disease.”
Powers and her documentary Twitch, which follows her as she decides to get tested just after she turns 18, are evidence of the phenomenon that Wild describes. It will likely take time before that culture influences genetic testing rates or research participation, but there’s clearly a shift underway.
For Carroll, it’s hard to find the right words to describe his dual experience as a prominent HD researcher and a carrier of the disease himself. “For me, it’s like all interesting stories: There’s something terrible about it or else it wouldn’t be that compelling — you know what I mean? I fairly regularly have these moments, usually when I’m out at an HD conference doing something with patients or the scientific community, of intense emotional awareness that’s really hard to describe. It’s like something that’s two colors at once, because it’s incredibly exciting and motivating and real and also horribly destructive and terrible. There’s no separating those colors. There’s no prism to spread it out. It’s just horrible and wonderful and a pretty neat job.”
His 10-year-old twins keep him busy with normal, everyday distractions that kids bring. They are “miracle babies,” conceived by in vitro fertilization. A genetic screening procedure performed prior to embryo transfer, known as preimplantation genetic diagnosis (PGD), means that they were born with absolutely no risk of developing HD.
“Without that screening,” Carroll says, “I would think about this every single time I looked at them.”
While PGD has been a godsend for Carroll and his kids, it’s a costly procedure that remains unavailable to many. Carroll is painfully aware that other members of his extended family and many other people around the world remain at risk. And so, in his Western Washington University lab, he and his trainees have been busy generating mice lacking HTT in various organs outside of the brain, including liver and fat, to explore what the protein does in other parts of the body and whether lowering levels of HTT in those organs would ameliorate HD signs. So far, the answer appears to be no.
“[But] we can’t get complacent,” he says. “We have to keep working.”
“Huntington’s was really the canonical condition where you would
lock up your own mother in a mental asylum rather than talk about it openly — not just with friends and acquaintances, but with members of your own family.”
Why aren’t more at-risk people tested for HD?
When asked, many people at risk for HD say they intend to undergo genetic testing to learn their status. But, in reality, most people don’t. Estimates suggest only 10 to 20 percent of people approached about testing decide to go through with it.
Why? Some people avoid testing out of fear or uncertainty about how or whether they’ll cope with the findings. Some worry that a positive test result might leave an HD-affected family member feeling guilty. Still others voice concern about what a positive test result would mean for health insurance or job prospects.
For Kristen Powers, there was never a question about whether she’d get tested. She even documented her experience preparing for and undergoing the test in her senior year of high school in a film called Twitch (twitchdocumentary.com). She says in her case she felt “the uncertainty was killing her.” Before she knew her status, she was always distracted with the question about whether she had the mutant gene or not.
At the end of the film, as in life, her test result ended in good news. She is HD-free, although she doesn’t know about her brothers and that still weighs on her mind. Powers was told prior to testing that it would take a year to fully process the test result, no matter which way it went. She didn’t believe it, but it proved true. As she explains, she’s had to come to terms with the fact that she’s a “normal person” who could die of anything.
In a class assignment in college, she was asked to design her life, and what struck her most was the realization that she had a single life list. In the past, she always had two: one for if she didn’t carry the HTT mutation and one for if she did. In many ways, she says, if she actually had HD, her future might feel more certain. For instance, under that scenario, she wouldn’t have wanted kids, even if they were adopted. Now that she knows she’s healthy, she isn’t sure.
For Jeff Carroll, too, testing was always a question of when, not if. He waited until the time was right, and then he got tested. Unfortunately, in his case, the news wasn’t what anyone would hope to hear. Still, he bristles at the notion that there’s not much you can do today with a positive HTT test.
“You can stay informed and engaged and participate in research studies,” he says. “You can be ready to be [among] the next set of people in the next [clinical] study.”
For those at risk who don’t know their status, it’s still possible to get involved and help out. Enroll-HD (enroll-hd.org) is a multinational observational study looking to enlist up to 20,000 people around the world who either have HD or are known to be at risk.
“We are really lucky. We were one of the first genetic disease communities to have the underlying mutation mapped. We were among the first
people to know that this bit of DNA causes the disease and to be able to test for that.”