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CAMBRIDGE, Massachusetts ‒ For decades it’s been one of the defining mysteries of Huntington’s disease. Why does the terrible devastation of mind and body start earlier in some people who inherit it and later in others?
Now a pair of scientists at a research institute affiliated with Harvard and MIT believe they’ve found an answer in the speed at which the genes of these people make mistakes.
This result, published Thursday in the journal Cell, isn’t just academic. It has implications for people who know they carry the dreaded gene but don’t yet know when symptoms will descend and normalcy will end. It suggests the treatment approach tried with mixed success in recent years isn’t the only way to disrupt the disease ‒ and it lays a clear path for what may be a better one.
Huntington’s disease, which affects about 30,000 Americans, is a fatal, inherited disorder that causes progressive movement, psychological and cognitive problems.
If a parent has it, their children have a 50-50 chance of developing it. But the severity and age it arrives has seemingly been up to luck. The new study shows the luck lies in the rate of genetic errors made over the course of the person’s lifetime.
If the errors accumulate relatively quickly, the person might get symptoms beginning in their 30s or 40s and die, typically 10 to 15 years later, becoming a tremendous burden on their family in the interim. If the mutations accumulate slowly, symptoms might not arrive until their 50s, 60s or beyond. The super unlucky ones get sick in childhood.
“It’s hard to accurately describe how devastating Huntington’s disease is in a sentence or two,” said Dr. Erin Furr Stimming, a Huntington’s disease expert at UTHealth Houston, who was not involved in the new research. “Because it affects individuals in the prime of their life, they are often unable to work and therfore they are unable to support families. Their children are at risk. Their children are caring for them. It’s a relentlessly progressive disease.”
What is Huntington’s disease?
The most well-known person with Huntington’s Disease was singer-songwriter Woody Guthrie, author of “This Land is Your Land,” who died in 1967 at age 55.
Although treatment of symptoms has improved since then, there are no drugs that alter the inevitable course of the disease, Furr Stimming said.
As was discovered in 1993, the disease is caused by a mutation in a gene called Huntingtin, which is necessary for brain development and to maintain brain cell function.
People who inherit the disease seem perfectly normal early in life. Except in the very rare case of childhood onset, it is impossible to tell who will develop the disease and who won’t.
In everyone, the genetic alphabet that spells out the Huntingtin gene contains a repeat of the “letters” CAG ‒ typically as many as 25 times in a row.
But people who inherit the disease are born with more repeats of this sequence, usually 40 times or more.
What the new study showed
The new research examined brain tissue from people who died from Huntington’s, provided by the Harvard-affiliated McLean Hospital. Newer technology allowed researchers to analyze the structure of individual genes within single cells in dozens of brains from healthy and affected donors.
The new study shows that in people with the disease mutation, this repeat accumulates in certain brain cells over their lifetime and only becomes toxic when it’s repeated 150 times or more, Steve McCarroll, the Broad Institute scientist who led the new research, said on a recent call with reporters.
In biology, as genes make proteins, they briefly “unzip” their double strands, so RNA can be made from the DNA instructions. When the two strands are matched up again, sometimes they make mistakes, like a jacket zipper with mismatched teeth.
For some reason McCarroll and his team still doesn’t fully understand, in people with Huntington’s Disease, the repair mechanism that tries to fix these broken zippers on their Huntingtin gene end up adding extra CAG repeats. It’s like one side of the zipper keeps getting longer, while the other doesn’t.
Even in people with the mutation, it usually takes decades for these mistakes to accumulate and CAG to reach 150 repeats, he said. But once it hits that threshold, it takes just “months for it to go crazy above 150.” The toxic load then becomes too much for the brain cell to manage and it dies, triggering horrible symptoms.
“We’re working to understand exactly what it is that’s changing at about 150 repeats that then causes these dramatic changes in a neuron’s health,” he said.
Implications for treatment
Most of the treatments currently under development focus on lowering the amount of protein produced by the mutant Huntinton’s gene.
But if that protein isn’t really a problem until after the gene passes the 150 threshold, at which point it quickly kills the neuron, and not every neuron reaches toxic levels at the same time, the drug doesn’t have much of a “window” in which to do its work, said McCarroll, director of genomic neurobiology at the Broad and a professor at Harvard Medical School.
An approach that might make more sense ‒ though his team has yet to test it in people ‒ is to slow down the accumulation of CAG repeats, he said. Other diseases, such as inherited ALS and Fragile X, are also caused by genetic repeats and this work could also help explain how those develop, he said.
Furr Stimming said the new study should also help people who have a family history of the disease and want to know if they are likely to get it and when.
Though it has been possible since 1993 to tell someone whether they are doomed to develop Huntington’s, it’s only in recent years that doctors have been able to count the number of CAG repeats and guess whether they are likely to get it sooner or later. The new paper should help refine that guess, she said.
“Unfortunately, we can’t accurately answer: ‘When will I become symptomatic and what will my rate of progression be?'” she said. “This paper along with other more recent findings is important in helping us better answer that question.”
Karen Weintraub can be reached at kweintraub@.com.
“The point of our work — what we all do — is relieving suffering caused by disease,” said co-senior author Sabina Berretta, associate professor of psychiatry at Harvard Medical School and McLean Hospital, a member of the Mass General Brigham healthcare system. She is also the director of the Harvard Brain Tissue Resource Center (HBTRC), an NIH NeuroBioBank center at McLean Hospital. “This study and the work it informs could be impactful and make a major difference in relieving suffering in the short term.”
Repeat expansion
To answer these questions, the research team built upon a technology the McCarroll lab developed a decade ago called droplet single-cell RNA-sequencing (Drop-seq), which allows researchers to analyze gene expression in thousands of single cells. Seeking to understand the direct biological effects of CAG-repeat length, the researchers adapted single-cell RNA-sequencing to help them determine not only gene expression and the identity of single cells, but also the length of DNA repeat tracts inside each cell.
The researchers studied brain tissue donated by 53 people with Huntington’s and 50 without the disease, collected and preserved by the HBTRC. They analyzed more than 500,000 single cells and found that most cell types from people with the disease had essentially the same CAG repeat that they had inherited. But striatal projection neurons — the primary striatal cells that die in the disease — had greatly expanded their CAG-repeat tracts. Most previous research on human brain tissue had focused on CAG-repeat tracts of fewer than 100 repeats, but the new study showed that some neurons had as many as 800 CAGs, confirming a discovery made 20 years ago by Peggy Shelbourne at the University of Glasgow.
Most surprisingly, the research team found that expansion of the DNA repeat from 40 to 150 CAGs had no apparent effect on the neurons’ health. But neurons whose repeats exceeded 150 CAGs showed greatly distorted gene expression, losing expression of critical genes and then dying.
McCarroll’s team also used computer modeling of the experimental data to estimate the rate and timing of CAG-repeat expansion in striatal projection neurons. They found that CAG-repeat tracts initially grow slowly, expanding less than once a year during the first two decades of life. But when a cell’s repeat tract reaches about 80 CAGs — usually after several decades — its rate of expansion accelerates dramatically and it expands to 150 CAGs in only a few more years. The cell then dies just months later. This means that a neuron spends more than 95 percent of its life with an innocuous HTT gene. Moreover, because the CAG-repeat tracts in different cells cross this toxicity threshold at different times, the cells, as a group, disappear slowly over a long period, starting about 20 years before symptoms appear and more quickly as symptoms commence.
“A lot was known about Huntington’s disease before we started this work, but there were gaps and inconsistencies in our collective understanding,” Handsaker said. “We’ve been able to piece together the full trajectory of the pathology as it unfolds over decades in individual neurons, and that gives us potentially many different time points at which we can intervene therapeutically.”
Analyzing brain tissue contributed by Huntington’s patients was critical for the work. “Our gratitude is with the families that chose to do something that is very difficult to do,” Berretta said. “This would not have been possible without the altruism of many brain donors who have left a legacy of knowledge that will last and benefit many other people.”
Therapeutic possibilities
McCarroll’s team suggests that rather than targeting the HTT protein, a complementary or potentially better therapeutic approach could be to slow or stop the DNA-repeat expansion, which could help delay or even prevent the disease.
Previous genetic studies of Huntington’s, including studies by Vanessa Wheeler and Ricardo Mouro Pinto at Massachusetts General Hospital, hint at possible ways to slow this expansion. The studies showed that cellular proteins involved in maintaining and repairing DNA sometimes undermine the stability of DNA-repeat tracts. For example, the MSH3 protein normally helps the cell monitor its DNA for potential mutations, but loops in the DNA formed by extra CAGs can confuse this protein into expanding the CAG repeat. An international team of human geneticists found that common genetic variations in the genes encoding these DNA-repair proteins can hasten or delay onset of symptoms in Huntington’s patients — findings that McCarroll says directly inspired his team’s focus on developing ways to measure the CAG repeat in single cells. He adds that slowing down certain DNA-maintenance processes with a molecular therapy might slow down DNA-repeat expansion by allowing other less error-prone DNA-repair mechanisms to resolve these loops.
In the meantime, the researchers are working to understand how DNA-repeat tracts longer than 150 CAGs lead to neuronal impairment and death, and why repeats expand more in some kinds of neurons than in others. They are also using a similar combination of single-cell RNA sequencing alongside DNA-repeat profiling to understand the connection between DNA-repeat expansion and cellular changes in other genetic disorders involving DNA repeats and late onset in patients. More than 50 human brain disorders, including fragile X syndrome and myotonic dystrophy, are caused by expansions of DNA repeats in various genes.
“It’s going to take much scientific work by many people to get to treatments that slow the expansion of DNA repeats,” McCarroll said. “But we’re hopeful that understanding this as the central disease-driving process leads to deep focus and new options.”
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Funding
This work was supported by CHDI Foundation, Inc., the Department of Genetics in the Blavatnik Institute at Harvard Medical School, the Ludwig Neurodegenerative Disease Seed Grants Program at Harvard Medical School, and the National Human Genome Research Institute of the National Institutes of Health.
Paper cited
Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease. Cell. Online January 16, 2025. DOI: 10.1016/j.cell.2024.11.038.
