PERRY, N.Y. — Reminders of Huntington’s disease populate Tammy Stewart’s apartment. They are also glimpses into her future.
On the table beside the couch sit framed pictures of her dad, Roy, and one of her sisters, Debbie, who both died from the disease. The apartment’s second bedroom belongs to Stewart’s brother, Mike, who at 60 years old is in the late stages of the disease. He spends most of the day in either a hospital bed or a reclining chair. He struggles to speak, his hands shake and ball up, and he relies on Stewart as a full-time caretaker.
Stewart, 46, also has the genetic mutation that causes Huntington’s. Tremors have started to trouble her hands and feet, and she has bouts of depression and flashes of rage. She sometimes loses track of what she is saying.
“If I’m at the beginning stages of it now, my quality of life with stress and stuff will go down fast,” she said. “And I don’t want that. I don’t want to live like that. I don’t.”
Stewart hopes she now has the opportunity to avoid that fate, or at least postpone it. She is one of about 800 patients around the world enrolled in a final-stage clinical trial of a drug designed to slow — maybe even stop — the progression of the disease. Though it wouldn’t be a cure, it’s the first time a therapy aimed at the actual root of Huntington’s has reached this far in its development odyssey. And it is one of a wave of therapies to rely on advances in genetic medicine to combat previously untreatable inherited diseases.
But for every patient who enrolls in the trial, there are others who have been left banging at the door, unable to participate because they don’t fit certain criteria, or they live too far away from a trial site, or the slots are already filled. Stewart was fortunate; she’s not too old or too young, she has started to show symptoms but they are not too advanced, and she doesn’t have other health issues.
There are reasons for such strict criteria, as there are with all clinical trials, which are meant to test whether the therapy in question is even effective. These are research studies that can only include so many people, after all, so investigators are looking for patients who are most likely to reveal any potential benefits of experimental treatments.
But to patients with diseases like Huntington’s, trials look like the best — and really, the only — option. They know trials have to have limits; that doesn’t make it easier when they’re told there’s no spot for them.
“We just wanted that opportunity to at least feel like we were fighting,” said Heather Thurgood Wilmoth, whose husband, Nathan Wilmoth, was turned away from the Huntington’s trial earlier this year because his body fat level was too high. “The feeling like we’re able to fight, along with that hope — we felt like that was swept out from under us. And let’s face it: With Huntington’s, it’s a hopeless disease.”
As a participant, Stewart, of course, might be receiving a placebo, as is the case with some patients in the trial, which will last for two years. The drug, from the Swiss pharma company Roche, could also end up being a bust. But having a chance to help secure a treatment for the disease, one that has loomed over her life since her father was diagnosed when she was 6 years old, has strengthened her resolve.
“I feel it in my heart that this was finally my purpose, because I’ve been wandering around not knowing what to do, or what my sense in life is if I was just going to die,” she said.
She has another motivation as well. On another wall in her apartment is another set of framed photos: Her three sons — ages 18, 19, and 21 — all at risk of the disease.
Huntington’s disease pockmarks family trees. As it slinks through generations, it spares some siblings and afflicts others.
The pattern offers a simple yet cruel distillation of the way the variant of a gene we inherit can shape our lives: If you have a parent with the mutation, you have a 50-50 shot of having it, too. If you do, you will develop the disease, and, assuming you don’t die of something else first, its complications will kill you. The disease spoils the brain and brings with it symptoms of Alzheimer’s, Parkinson’s, and ALS, all wrapped up in one.
The mutation lies in the HTT gene, which contains the instructions for making a protein called huntingtin. Scientists don’t fully understand all the protein’s roles, but it’s somehow involved in brain development. What scientists do know is that when there’s a mutation in the gene, the resulting protein clumps together and — in another process experts haven’t delineated — kills neurons. The disease’s first targets are areas of the brain that regulate behavioral and emotional control and orchestrate movement.
Symptoms typically arrive in people’s 30s or 40s — after they may have already and unknowingly passed on the mutation to their children. Irritability and depression are typically followed by tremors and reduced coordination. Patients eventually lose the ability to walk, speak, and swallow. They undergo personality changes and withered cognitive function. Death generally comes 15 to 20 years after the first symptoms.
An estimated 30,000 people in the United States have the disease.
Patients can take antidepressants and antipsychotics and anti-anxiety medications; there are drugs that help control the stumbling and jerking movements called chorea, which sometimes lead others to think people with the disease are drunk. But there is no treatment that can slow or delay the disease’s progression.
Unlike the errors that cause such diseases as sickle cell and cystic fibrosis, the mutation behind Huntington’s is not a misspelling in the “letters” — A, T, C, and G — that make up DNA. Rather, it is an “expansion.” In the HTT gene, everyone has a certain number of repeats of the letters CAG. Thirty-five or fewer of the repeats is healthy. Those with a few more may show symptoms of the disease late in life. People with 40 or more CAG repeats will get the disease.
Scientists do not know exactly why these extra CAG triplets engender a protein deadly to neurons. But they form an extra-long protein that becomes toxic. The more repeats a person has, the earlier the disease will tend to strike.
Breanna Lentz, a 13-year-old in Plainwell, Mich., has 80 CAG repeats — a rare case of juvenile Huntington’s. Her sister, Shelby, said the family thinks symptoms started appearing when Breanna was about 7. Now, she relies on a feeding tube and sometimes has to use a wheelchair. Her disease is so advanced that likely no drug could reverse the damage. But her family — and others in their position — are frustrated that juvenile Huntington’s patients are widely excluded from studies, including the Roche trial.
Among the reasons: The disease manifests differently in children, and moves more rapidly. Drug companies also generally don’t want to test their experimental treatments in patients whose brains are still maturing.
“‘Their brains are not fully developed until they’re 25’ — I hear that all the time,” Shelby said. “And I think, will their brains ever fully develop? Because when you have HD, it deteriorates.”
She added: “There’s not a lot for them to even have the opportunity to be a part of.”
Shelby, 22, went through genetic testing two years ago to find out if she had also inherited the Huntington’s mutation from their father. Some people avoid the test because they can’t face knowing they have a mutation that will eventually kill them. But she was adamant, and found out she had it as well. She has 49 repeats — a more common number among Huntington’s patients — and is not yet displaying symptoms.
On the other end of the spectrum from Breanna is Tom Marciniak, a retired Toledo, Ohio, firefighter. He was unable to enroll in the Roche trial in part because he is 70 — and the upper cutoff is 65. His family hopes that the drug succeeds in the trial and quickly gets approved by the Food and Drug Administration. That way, it could be available to all patients.
But the process will likely take at least three years, assuming everything goes smoothly. All the while, his condition will worsen.
“I guess we’ve resolved ourselves to the fact that he’s 70 years old, and we’ve had a great life, and whatever comes comes,” said Tom’s wife, Connie Marciniak.
Roche designed the trial to represent the large majority of people with Huntington’s, the company has said. It needed participants whose decline could be anticipated so researchers could assess the ability of the drug to serve as a brake. That excludes people who haven’t started to show symptoms yet. And it excludes people who develop the disease later in life because they tend not to show regular progression.
Roche also couldn’t include people with late-stage symptoms. In addition to the fact that the drug likely couldn’t make a difference, these patients couldn’t go through the rigor of participating: getting to the trial sites and completing all the questionnaires and tests required for the two-year course of the study.
“These are never easy decisions that we have to make in terms of enrollment criteria, and inevitably, when you run a large study, there are going to be people who are somewhat outside the enrollment criteria,” said Dr. Scott Schobel, the clinical science leader of Roche’s Huntington’s program, who called the level of patient interest in the trial “unprecedented.”
“We think it’s all in the service of generating the highest quality scientific results,” he added.
Then there are patients who think they are prime candidates, only to encounter something unexpected.
For years, Linda Briggs, 49, of Kitchener, Ontario, has been following the progress of the treatment, now called RG6042. She knew that if it reached clinical trials, and one of the study locations was close to her, she wanted to be a part of it.
Earlier this year, she thought she was set to achieve that goal. She went through the screening process at a trial center in the Toronto area, and completed the physical and cognitive tests. But then an MRI picked up a growth on her brain.
It was, as Briggs put it, “two bams in one: ‘Oh, you can’t be in the trial, and you might have cancer.’”
“It was, like, I’ve been looking forward to this for years,” she added. “I tried to do everything right. I kept my weight down and tried to eat right. But then one MRI and a bump on my head, and there you go.”
Briggs is still waiting to hear what exactly the growth is. As for the trial, she has tried to reframe her thinking. The trial’s success isn’t inevitable — though of course she hopes it is — and it’s possible she could have been enrolled in the placebo arm. She might look at other drugs in earlier stage trials, or perhaps Roche’s will eventually be approved. There are other treatments in development from companies including UniQure, Voyager Therapeutics, Vaccinex, and Wave Life Sciences.
The question is whether any of it will be enough. The disease moves slowly, but already, her coordination has started to slip, she forgets words, and has to eat slowly. She has watched some of her relatives turn mean and violent as the disease burrowed into their brains. She knows there could be periods of anxiety, memory loss, trips and falls and dropped objects.
“I would have been so proud to be a part of it,” she said about the trial. “I’ve seen so many of my aunts and uncles and cousins go through it, and I’ve been to so many funerals, and I wanted to do it for them, and for everyone in the future too.”
It has been 26 years since scientists traced Huntington’s to the HTT gene, raising the possibility of targeting the genetic root of the disease — and going beyond treating symptoms. At the time, the Los Angeles Times hailed the discovery as a watershed achievement following “the longest and most frustrating search in the annals of molecular biology.”
The Huntington’s community, in other words, has waited decades for this moment.
“There was a lot of hope when they identified the gene in ’93,” said George Yohrling, the senior director of mission and scientific affairs at the Huntington’s Disease Society of America.
Roche’s Huntington’s therapy, which has been developed in collaboration with Ionis Pharmaceuticals, is the result of discoveries that allow scientists to build treatments that manipulate and overcome errors in our DNA. Today, they know how to boost production of healthy proteins and to tweak or dampen a faulty gene, controlling genetic expression like a conductor leading an orchestra.
The Roche drug, specifically, uses a “gene silencing” approach.
To make a protein like huntingtin, cells rely on what’s called messenger RNA, which helps translate DNA’s instructions into a language the cell’s protein factory understands.
Roche’s treatment, called an antisense oligonucleotide, is a piece of synthetic DNA that is designed to swoop in and bind to the mRNA. That signals the cell’s destruction mechanisms to chop up the mRNA so that it can no longer go on to make huntingtin.
At the trial sites, the treatment is injected into the fluid that bathes the spinal cord, allowing it to be shuttled to the brain.
In an early-stage, 46-patient trial, researchers found RG6042 lowered the levels of mutant huntingtin in patients’ cerebrospinal fluid, with higher doses corresponding to a greater reduction in the protein. The final trial will examine whether that reduction slows — or even stops — the progression of the disease.
Mark Adler, 33, has been traveling from his home in Philadelphia to Washington for his injections. His father and uncle died from Huntington’s, and he has a brother and cousin with advanced cases. Another brother killed himself. Though he had never been tested, he had been showing signs of what the family thought must be Huntington’s, including depression, and struggled with substance misuse, Adler said. The suicide rate among people with Huntington’s is estimated to be up to 10 times higher than the national average.
Adler has thought about how Freddie Mercury died from AIDS complications in 1991, the same year Magic Johnson was diagnosed with HIV. HIV and Huntington’s are very different conditions — one an infectious virus, one a genetic disease — but Adler has wondered whether one of the drugs in development could do for Huntington’s what treatments have done for HIV: turn it into a treatable condition instead of a fatal one.
“If all this stuff had come 15 years earlier, my whole family might be here,” Adler said. “Then again, I could say if it came 10 years later, then I might not be here at all. I can’t even wrap my head around how down to the wire it is for me.”
When Nathan Wilmoth — the patient whose body fat level disqualified him from the trial — was turned away, it felt like another blow, the latest piece of bad news since he and his family learned more than three years ago that he had the mutation.
But a few months later, Roche rejiggered the injection schedule for the trial, which allowed him to be assessed again. Nathan had happened to lose some weight by then, and he passed through the screening process.
Now, he and Heather drive the 3 1/2 hours from their home in Mississippi to Birmingham, Ala., every eight weeks for his injections.
“We get that this may or may not work,” Heather said. “We understand that. But at least we feel like we’re fighting. We know what the alternative is. And if this doesn’t work for us, at least we’ll know what doesn’t work, so that’s one step closer to them finding something that does work.”
A few years ago, Nathan, 41, had to leave his job as a diesel mechanic; dropping and breaking $600 parts wasn’t going to work. They joked that he now spends his days with his “girlfriends,” Netflix and YouTube.
But he has two kids, 4 and 14.
“We’re still able to do things with them, and to make memories with them, and that’s what’s important to us,” Heather said. “Nathan’s considered midstage Huntington’s, so it’s not like we’ve got a lot of time to wait.”
Very informative text, my wife is suffering from HD since last 10 years, she is 57 weighting 42 kg, thin built, we live in India 20 km from NEW DELHI. pl guide us next step to get recovery from this disease.
Thanks Andrew for writing about this disease. As you may know, the publicity and funding a disease gets is often the difference between finding or not finding cures or treatments. Thanks for calling attention to this somewhat rare but sinister, catastrophic and demoralizing disease that robs people of normal lives in their prime.
My youngest daughter lexi just turned 18 yrs old last yr in june Then got got the results from being tested that she has H.D, Same day she found out she was pregnant. She had to go to the childrens hospital for a full ultrasound on the baby girl to make sure she was fully developed. Thank gos she was. The 2 doctors asked us if she would like to get the baby tested they would do a easy way. But then they got a 3rd doctor for his input nd sadly they all agreed that they won’t do it. Like lexi her baby will have to wait til she’s 18 yrs old to get the results as well. They did a nation wide surveys about it and refuse to test under 18 and even babies Due to the amount of suicides caused from family knowing the outcome when someone has it! I’ve tried to get her tested at the childrens hospital in California-Oklahoma (3 diff towns in this state) it was all the same out come a NO. You can ask a pm care doctor to start the testing, brain mri scan, blood work and a doctor that specializes in it to start while under 18 yrs old but again no results until 18.. Hope this helps ppl understand why they won’t test under 18 or a baby. We wanted to know so we could be prepared for it. Were not suicidal family so nd we have 18 yrs to think about knowing. Her dad has it and it has not skipped any generation except a few here on there didn’t have it. Like her gma nd her twin had a total of 3 siblings which all had it but 2 outta 5 total. It’s a horrible disease I’ve seen it 1st hand and helped take care of both of them.. Her dad is showing signs nd refuses to get tested cuz he said if he found out he had it he would end it. (He don’t live with us he’s 1300 miles away).. Alot of ppl don’t even know what H.D. is hope they make awareness more public of all diseases like these So everyone can treat those who have them better and with respect then think they’re on drugs or pills or drunk..
Thank you from me and my family for this post… God bless you all.
My son Birthday was yesterday he is 57 years old n has Huntingtons . Please keep me informed, thanks
Very enlightening. Well written so that everyone can understand. Thanks, Karen
Newborns should be tested for HD, so that parents can choose to not have anymore kids, or to consider adopting children. So many inheritable diseases could be prevented from spreading, by hugely stepped-up preventative and already available diagnostics. It requires a vastly improved health care system, that would save billions in treatment and care costs. Really, this approach is a no-brainer for humanity’s strength and existence.
I find this comment terribly insensitive and offensive.
This article was very well written. I resent the person who says people should be genetically tested. Most all of us have some genetic abnormalities which are manifested in different ways. In the case of Huntington’s, testing wouldn’t help in every situation. Read the article again. It speaks of the gray area of around 35 CAG repeats. That could mutate higher through families. In addition, I want to ask: who are you to play “God” ? Very rarely are there any genetically perfect people. Something is going to end all of our lives. A genetic disease doesn’t define someone.
No need to test newborns. Most young adults know if they potentially carry the gene. If a grandparent has it, they have a 1 in 4 chance of carrying it. And if they have it, there is a 50-50 chance their newborn has it.
If I had a grandparent with HD, I would get a DNA test for the disease before deciding to have kids.
I have a niece and nephew with huntingtons. Their father was adopted and new about the disease being in his DNA. He passed it on to three children before he committed suicide. If children are tested at birth iT his disease could eventually be whiped out.
Very helpful article! My wife is 67 and was diagnosed 21 years ago. She is very advanced. We have 3 “at risk non-tested” children, all @ 40 y.o. with no symptoms, and a niece that is participating in the Roche study. Our 4 grandchildren were all the result of embryo implantation, virtually guaranteeing their immunity from the disease. ANY articles pertaining to HD is always helpful and HOPEFUL to our family. Thanks so very much
For any young person around the world who is impacted in some way by HD, please visit the Huntington’s Disease Youth Organization’s website to find support, proper education and empowerment! http://www.HDYO.org
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