Most clinical trials for Huntington’s disease have run aground in the last few years, but academic researchers haven’t been dissuaded from trying to shift how the rare genetic disorder is understood.
A handful of papers released in the last 12 months suggest those shifts are coming sooner rather than later. The latest scientific study,
published in
Cell
on Thursday
, comes from researchers at the Broad Institute of MIT and Harvard. They claim previous research may have been looking at the disease the wrong way and offer a potential new framework for treatments.
Led by Steve McCarroll and Sabina Berretta, the group looked at postmortem brain tissue of Huntington’s patients and compared it to tissue from individuals without Huntington’s, aiming to see how a specific DNA mutation influences the disease’s pathology. They assert, contrary to early assumptions, that Huntington’s patients don’t slowly deteriorate.
Rather, the mutation builds up and repeats in patients over time and then suddenly becomes toxic, leading to rapid decline.
“Once toxicity starts, it’s fast,” McCarroll said in a call with reporters last week. “It’s months, not decades. It’s about 100 times faster than we thought.”
McCarroll and Berretta’s group says it might be more effective, then, to treat Huntington’s patients before any toxicity appears in order to delay the disease’s onset — maybe indefinitely down the road. That could amount to a functional cure, where individuals with the genetic mutation never suffer from symptoms because they end up living normal lives and die from natural causes before their DNA becomes toxic.
But McCarroll cautions it’s still early days, and the paper offers few solutions to put new screening and drug development procedures into practice beyond the general idea that people who carry the mutant gene should be treated earlier. It’s also unlikely there will be any near-term clinical results for drugs targeting these underlying genetic errors at earlier stages in patients’ diseases. The most prominent company attempting to do so — Triplet Therapeutics —
shut down
in 2022.
Still, McCarroll says he has been encouraged by the interest he’s seen in some corners of the biopharma industry.
“It takes years of work to develop new therapies, but we’ve been sharing these results in the scientific community at conferences for a year and a half,” McCarroll said. “I think it’s fair to say that companies have been really interested in it. And I can’t speak for them, but I can say, broadly, many companies are starting or expanding programs to try to do this.”
Huntington’s researchers have known since the 1990s that the disease is caused by an inherited mutation in the huntingtin gene (HTT). The mutation causes a “triplet repeat,” where three letters in the HTT gene are erroneously duplicated over and over again and result in DNA mismatches that produce toxic proteins.
In Huntington’s, the letters that repeat are a sequence of CAG. Healthy individuals typically have HTT genes consisting of 10 to 35 CAG repeats, while anyone with 36 or more CAG repeats has the mutation and, as a result, Huntington’s disease.
But what McCarroll and Berretta found is that the mutation doesn’t become toxic until the CAG sequence repeats 150 times, which can take decades.
It’s an assertion that fits within what’s been known about Huntington’s, given that most patients only start presenting symptoms between the ages of 30 and 50.
After the discovery of the HTT gene in the 1990s, the conventional wisdom held that the mutation progressively caused brain cells to die off slowly, accumulating enough for Huntington’s symptoms to usually start appearing by middle age. Drug developers, in turn, largely tried to make treatments designed to reduce the buildup of the toxic mutant Huntingtin proteins. Some successfully did reduce the buildup, but patients still weren’t improving.
Other recent attempts, such as Roche and Ionis’ antisense therapy tominersen, tried to reduce the buildup by interfering with the RNA that encoded such toxic proteins, preventing the mutated DNA from killing more neurons. In 2021, tominersen
flopped
a Phase 3 study in perhaps the field’s most
high-profile setback
. (The companies have since
launched
a new Phase 2 trial aiming to enroll younger patients.)
The McCarroll-Berretta paper implies that those approaches were essentially doomed to fail, because they attempted to treat patients after the rapid toxicity began. By getting therapies to patients earlier, namely before their CAG sequences reach 150 repeats, developers could ultimately be more successful in treating Huntington’s.
Irina Antonijevic, the former chief medical officer of Triplet Therapeutics, which was attempting to develop antisense and siRNA drugs for Huntington’s, told
Endpoints News
in an interview last summer that the theory behind their paper — how toxic repeats with runaway expansion drive Huntington’s pathology — had been floated for some time. Not everyone was on board immediately, she noted.
“When this was first discussed more than 10 years ago, it was pooh-poohed,” Antonijevic said.
Over time, more scientists eventually started noting the theory’s merits and tested whether it held up. But to claim a specific toxicity threshold and prove it in an experiment using human brain tissue, which McCarroll and Berretta did in their study, is “mind-blowing,” she said.
“This paper takes it even further to say, “What is the threshold?” Antonijevic said. “‘How long do the repeats have to be to really become detrimental for the cells?’”
Triplet Therapeutics’ approach came the closest to what the new paper describes, not just for Huntington’s but other genetic disorders with triplet repeats (hence where the startup got its name). The company aimed to target a gene called MSH3, which is involved in DNA mismatch repair, with its lead antisense program for Huntington’s. Ideally, the drug would have knocked down the MSH3 gene to prevent the CAGs from expanding and delay the onset of symptoms.
But the drug never started clinical trials.
Triplet ultimately shut down in late 2022 after the Roche failure and the broader biotech downturn cast a chill over Huntington’s development. The company was unable to raise a Series B round after bringing in a $59 million Series A in 2019.
Former CEO Nessan Bermingham told Endpoints the new paper validated the company’s work, but said there’s still more that needs to be done, such as designing a clinical trial for people who carry the mutation but don’t have symptoms.
“When you intervene, do you need to really intervene before they show any phenotypic representation of the disease?” Bermingham said. “Or when you start to see the actual disease present or manifest?”
McCarroll and Berretta’s paper comes about a year after researchers in the UK, led by Gillian Bates at University College London, published
their own Huntington’s paper
in
Brain
using mouse models and came to a similar conclusion: Earlier treatments for Huntington’s are likely to be the most promising, and MSH3 is currently the most viable target.
The Bates paper also argues that the rate of disease progression is capped after the CAG sequences surpass 185 repeats, and that treatments trying to prevent more expansion will be completely ineffective if given after this time. But the papers differ in one key aspect.
Bates contends that CAG repeats in the brain are not a requirement for Huntington’s to develop, given what’s known about how the disease develops in young children. She and her colleagues note how, in extremely rare pediatric cases of Huntington’s, infants who present with symptoms before they turn 2 years old are born with mutant sequences of at least 200 CAG repeats — which typically takes decades to happen in older patients.
Asked what he thinks about the differences between their two papers during the call with reporters, McCarroll essentially demurred: “Our results suggest that [the CAG repeats] are necessary and sufficient,” he said.
Bates declined to comment for this story, citing scheduling difficulties.
