Amanda Miller had never cried in front of the guys at the pizza parlor before. Sure, they were a tight crew — grilling out back during their breaks, hanging out between shifts — but Miller was the strong one. Stoic.
Yet on that day, nearly 15 years ago, she sobbed, knowing her life would never be the same. Moments before, her parents had arrived and told her the news — her dad was diagnosed with Huntington’s disease, and Miller had a 50% chance of getting the disease.
“It felt like I was losing my dad and my future at the same time,” Miller said, “If it weren’t inherited, it wouldn’t have been the same.”
Huntington’s disease is one of the worst conditions known to humankind. Those who know it well call it a triple-threat, because it combines symptoms of Parkinson’s, Alzheimer’s, and Lou Gehrig’s all in one.
It strikes adults in their forties, attacking the brain cells and steadily deteriorating their physical, mental, and emotional functions until they die. Currently, there is no cure.
Even worse, the disease doesn’t just strike once — it attacks entire families.
Researchers have pinpointed Huntington’s disease to a single gene, so the inheritance pattern is well understood. If one parent has the disease, every child has a 50/50 chance of also having it.
For Miller, that meant she, her sister, and her brother were all at risk — as is her son — something they will live with for the rest of their lives.
“I just keep thinking over and over again throughout my life — flip a coin. Heads, I have it. Tails, I don’t. It is just looming,” Miller said.
Miller was in her 20s when her dad was diagnosed. For the next decade, she was by his side as he lost the ability to do everything he loved, like fishing, camping, and hunting. As a mechanic, he could fix anything — taking engines apart and rebuilding them from scratch. But eventually, his hands weren’t steady enough, and he couldn’t keep track of what went where.
He was the type of man who had a joke for everything, but even his personality changed, bringing in bouts of obsession, depression, and frustration.
The decline in physical, emotional, and mental abilities Miller’s dad experienced is the disease’s hallmark. Uncontrollable muscle movements, loss of coordination, personality changes, and dementia gradually take over the body and mind, getting progressively worse.
Eventually, people lose the ability to walk, eat, and even talk. Yet, people are often painfully aware of their own decline.
“It’s awful — you can watch someone you love deteriorate, just knowing that it could be you too,” Miller said.
Would You Want to Know If You Had a Death Sentence?
In 1993, a team led by geneticist Nancy Wexler identified the genetic mutation that causes the disease by working with a population in Lake Maracaibo, Venezuela, which has the highest concentration of Huntington’s disease in the world, due to inbreeding.
Pinpointing the gene opened up opportunities for new research and for people who are at risk to take a simple genetic test to find out, with certainty, if they will develop Huntington’s disease or if they are in the clear.
But, like most people who are at-risk, Miller has no plans to get the test.
90% of people who know they are at risk for Huntington’s choose not to take the genetic test — mainly because there are currently no Huntington’s disease treatments available. If they test positive, they can’t “undo” that knowledge. Living with the Huntington’s “death sentence” is harder than living with the unknown.
Overall, genetic testing is becoming more common. Pregnant women are routinely offered genetic screening to test for some diseases that the baby could have. Direct-to-consumer (DTC) genetic tests, like those from ancestry.com or 23andMe, which are popular for understanding a person’s ancestral history, can also provide insight into the risk of some diseases, like Alzheimer’s or heart disease.
But neither will test for Huntington’s disease, because of the heavy burden of receiving a positive result. Unlike a genetic test for Huntington’s disease, the consumer kits generally only reveal a slight change of probability for inheriting a disease. That is because most conditions involve many genes. But it only takes one gene to develop Huntington’s disease, and a positive test is a guarantee.
Additionally, people who are at risk for Huntington’s disease face the possibility of genetic discrimination. Although the Genetic Information Nondiscrimination Act was passed in 2008 to protect people, there are loopholes. For instance, long-term care insurance companies can ask about and deny coverage based on your family history of Huntington’s disease.
And many people keep that information private because of the potential for employment discrimination. When Miller landed her first teaching job, she was asked to complete a health insurance coverage checklist. She will never forget one question, which directly asked about her Huntington’s disease status — reinforcing her decision not to get tested.
“Until there’s a cure or a way to slow this down, there’s no point. (If I carry the gene,) it can only harm me to know,” Miller said. She isn’t alone. The close-knit Huntington’s disease community is waiting for a scientific breakthrough that stops neurodegeneration.
With new research in the pipeline, some studies progressing forward and others coming to an end, the Huntington’s community is riding an emotional rollercoaster of hope and loss.
Curing the Incurable
Ever since Wexler discovered the HTT gene, which is responsible for the disease, scientists have been trying to find a cure.
The HTT gene provides instructions for making a protein called huntingtin. Everyone has this gene and the resulting protein. But people with Huntington’s disease have a faulty version of the gene, which creates a mutant protein that appears to play a role in the decline of nerve cells in the brain.
Most researchers believe that the presence of the distorted huntingtin protein, not the faulty gene by itself, is to blame for brain cell dysfunction. This raises the possibility that you could stop the disease, even if you can’t fix the original broken gene.
At least 23 companies are taking a shot at therapies that lower the mutant protein. Nearly all of them are in the pre-clinical phase. Three companies have enrolled human patients for a trial.
The farthest along was Swiss pharmaceutical giant Roche — with 800 patients enrolled in the study. Until 2021.
Hope and Loss
Ask anyone in the Huntington’s community what “Roche” means to them, and they will likely say “hope.”
But, on March 22, 2021, Roche made a heartbreaking announcement: they were halting the study early, providing very little details on why.
The study involved an investigational drug discovered by a team led by Frank Bennett, a neurologist and chief scientific officer at Ionis Pharmaceuticals. It stopped cells from producing the mutant huntingtin protein.
I talked to Bennett about a week before the study was canceled. I can still hear the hope in his voice.
He described talking to a close friend who is at risk for Huntington’s disease. When Bennett shared his preliminary data with his friend — among the most promising ever seen for Huntington’s — showing how the drug lowers the huntingtin protein in the central nervous system, it transformed his friend’s life.
It would be a miracle for the community to have any disease-modifying therapy.
Erin Furr-Stimming
Instead of planning his future based on Huntington’s disease and the inevitable impact it was going to have on his future and family, he started planning on living a full life.
“It sounds trivial, but it’s a sea change in how to think about your future,” Bennett said. He anticipated the study would conclude next year, and we would learn then if the treatment is effective.
Miller, around the same time, echoed the sentiment.
“When (Roche’s treatment) gets approved, I’m going to get tested for the gene right away, because it is either going to eliminate a lot of anxiety if I don’t have it, or I can start treatment if I do have it,” she said.
But it was only a few weeks later that 15 years of work and hope — from drug discovery to human trials — unexpectedly came to an end.
For Miller, the study’s cancellation is crushing.
“I felt like it was our biggest hope that the whole Huntington’s community has been waiting on and paying close attention to — this study in particular. I feel like I’m going through the stages of grief with this. It feels devastating,” she says.
But Bennett, meanwhile, remains committed to finding a Huntington’s disease treatment. Ionis, his company, has seen success with similar types of drugs in the past. They have an approved drug for a disease that was the most common genetic cause of infant death and currently in clinical studies they have six other medicines that address neurodegenerative disorders. Despite the setback, he is optimistic about the future of Huntington’s disease treatments.
“Fortunately for the patients, interest in finding therapies for HD (Huntington’s disease) patients has increased over the past several years, with multiple companies, including Ionis,” he said in an email, “so they should not give up hope.”
He warns people not to draw any conclusions until the full data from the study is analyzed.
“It Would Be a Miracle”
Since Roche has dropped out of the race, uniQure has taken the lead. On April 5, the Massachusetts-based company announced they had completed enrollment for the first cohort of human trials, which will test their early stage Huntington’s disease treatment.
Cells translate protein-making instructions from DNA to RNA and deliver them to ribosomes, the cell’s protein factory. This is where researchers at uniQure believe they have come up with a possible solution. Their strategy aims to lower the mutant huntingtin protein, by interrupting this process and stopping cells from making the protein altogether.
To do that, researchers at uniQure reprogrammed a virus to deliver a special piece of DNA to the nerve cells, which will stick to the mutant RNA and block it from being turned into the bad protein.
Last year, in the midst of the pandemic, they injected the engineered virus directly into the first volunteers’ brains, through a hole drilled in the skull.
Erin Furr-Stimming is a movement disorder neurologist at the University of Texas, one of the uniQure trial sites. She screens patients before their brain surgery and monitors their progress after. Each volunteer received either the actual treatment or a “placebo” — small burrs drilled into the skull but no viral vector injection.
“HD is such a horrific disease. Folks are willing to do whatever it takes,” she says.
At the end of the year, doctors will look for signs of neuro-decline in the 10 patients. In the best case scenario, if everything goes as they hope, the treatment could stop the neurodegenerative decline in its tracks.
“It would be a miracle for the community to have any disease-modifying therapy — any compound that actually appears to slow or even better, halt the disease progression,” Furr-Stimming says, adding that she is cautiously optimistic. “It is a very exciting time for HD-related research. We have multiple disease-modifying trials right now.”
“You Just Keep Hoping”
The Huntington’s community is no stranger to the emotional rollercoaster of optimism and loss. Miller has been there many times before — 15 years ago, when she first learned she was at risk; then when her father died; and again when the Roche study was cancelled. But, somehow, she finds a way to move forward.
“You just deal. You don’t have much of a choice. You just keep hoping that something positive will come out of it, they’re going to learn something,” she said.
But, despite the setbacks, the potential Huntington’s disease treatments that remain, which are all in trials, still offer a unique kind of therapy for the Huntington’s community, which research shows can impact a person’s happiness, motivation, and health — hope.
“It makes a huge difference on the outlook — the emotional toll of it. Having either a cure or something to slow the progression down can make such a big difference in what your life looks like,” said Miller.
It’s incredible how hope for a different fate tomorrow can make today a little better.
UPDATE: Despite saying she had no plans to get tested for the gene that causes Huntington’s disease, Miller eventually changed her mind. Her test results came back positive, which she announced on Twitter, confirming that she does have the gene and will ultimately develop the disease. This news deeply saddens me. I am grateful I got to know Miller while working on this story and that she was so open to sharing her journey.
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