The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Dr. Cristina Sampaio
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”