Huntington’s Disease

Huntington's disease is caused by a CAG DNA repeat that can keep growing inside brain cells over a lifetime, and two proteins, MLH1 and FAN1, help control how fast it expands. Scientists worked out the detailed three-dimensional structure of how these proteins lock together, uncovering a previously unrecognized contact point between them. Because slowing this repeat expansion is now a leading strategy for future treatments, mapping exactly how these proteins interact gives drug developers a precise structural target to aim at.

In Huntington's disease the balance of activity in the brain's outer layer (the cortex) becomes disturbed as certain calming, inhibitory nerve cells misfire. Using advanced imaging in mice, researchers pinpointed which cell types drive this imbalance and showed that restoring the normal braking signals eased disease-related behaviours. The work suggests that correcting cortical circuit dysfunction, not only targeting the mutant protein, could help relieve symptoms, and it points to specific cells worth exploring as future treatment targets.

Inflammation inside brain cells contributes to the damage of Huntington's disease. This study focused on cGAS-STING, an immune alarm system that senses stray DNA and switches on inflammation. In mice carrying the Huntington's mutation, genetically switching off cGAS improved movement problems and reduced harmful signalling. The findings support the idea that calming this inflammatory pathway could protect neurons, and they highlight cGAS-STING as a potential drug target to complement approaches that lower the mutant huntingtin protein itself.

Cells rely on recycling systems to clear away toxic proteins, and in Huntington's disease this housekeeping breaks down. Researchers studied SIDT2, a protein that helps degrade DNA and RNA and that can bind and lower the mutant huntingtin message. They found SIDT2 accumulates abnormally in the brains of people with Huntington's, marking it as a new feature of the disease. Understanding this waste-clearance pathway may reveal ways to help cells dispose of the harmful huntingtin they cannot otherwise remove.

Many experimental treatments aim to lower the clumps of mutant huntingtin protein that build up in the brain, but doctors need a way to see whether they are working. This study tested a radioactive tracer, [18F]CHDI-385, that lights up huntingtin aggregates on PET brain scans in mice. The tracer reliably detected the clumps, suggesting a similar scan in people could one day track whether a therapy is clearing the toxic protein, which would speed the testing of disease-modifying treatments.

The involuntary movements (chorea) of Huntington's disease are commonly treated with VMAT2 inhibitors, a group of drugs that includes tetrabenazine, deutetrabenazine and valbenazine. This analysis pooled results from several randomized trials to weigh how well these medicines reduce chorea and how safe they are. Overall the drugs meaningfully lessened involuntary movements, with generally manageable side effects. The review helps patients and doctors compare current symptom-easing options while researchers keep working toward treatments that slow the disease itself.

This trial is testing SKY-0515, an oral medicine designed to lower the harmful huntingtin protein by adjusting how its gene is read. Adults aged 25 and older with genetically confirmed Huntington's disease who meet certain physical and independence criteria may take part. The study measures whether SKY-0515 reduces huntingtin, along with its safety and its effect on symptoms. It is one of several huntingtin-lowering programs now in trials. Ask your care team whether you might be eligible.

Votoplam (formerly PTC518) is an oral huntingtin-lowering drug that changes how the HTT gene is spliced so cells make less of the mutant protein. This phase 3 study is enrolling people with early symptomatic Huntington's disease to test whether votoplam slows disease progression compared with placebo, while checking safety and tolerability. Because it is taken by mouth rather than injected into the spine, it represents a potentially more convenient approach. Speak with your care team about eligibility.

Valbenazine is an approved once-daily VMAT2 inhibitor used to reduce the involuntary movements (chorea) of Huntington's disease. This study follows people in Canada who took part in an earlier valbenazine trial to gather longer-term information on its safety and tolerability. It enrolls by invitation, meaning only prior participants can join rather than being open to the public. It focuses on easing symptoms rather than slowing the underlying disease.

ALN-HTT02 is an investigational therapy that uses RNA interference, a natural gene-silencing process, to reduce production of the mutant huntingtin protein. This early-stage trial is evaluating the safety, tolerability, and biological effects of single or repeated doses in adults with Huntington's disease across sites in Canada and other countries. It is among the newer huntingtin-lowering treatments entering human testing. Whether taking part is right for you is a decision to make with your specialists.

GENERATION HD2 is testing tominersen, an antisense drug given by spinal injection that lowers the mutant huntingtin protein, in people with very early (prodromal) and early manifest Huntington's disease. After an earlier phase 3 study was stopped, this trial uses lower doses and focuses on earlier-stage participants to re-examine safety, biomarkers, and effect on the disease. It is no longer enrolling but continues to follow participants. Its results are expected to shape how huntingtin-lowering is used going forward.

SPK-10001 is an experimental gene therapy for Huntington's disease. It is delivered directly into the brain and is designed to durably lower the mutant huntingtin protein from a single treatment. This early trial is evaluating its safety, tolerability, and preliminary effectiveness in adults with Huntington's, and it includes a placebo (sham surgery) comparison. Gene therapies aim to change the disease's course rather than only its symptoms. Ask your care team whether a study like this could be an option for you.

AMT-130 is a one-time gene therapy in which a harmless virus delivers instructions into the brain's striatum to lower the mutant huntingtin protein. This first-in-human phase 1/2 study in adults with early manifest Huntington's disease, some receiving the therapy and some a sham (imitation) surgery, is assessing safety and early signs of benefit. Its interim results have drawn wide attention as a possible first disease-slowing treatment. It is no longer enrolling, but participants continue to be followed.

Enroll-HD is a large, worldwide observational study and registry for families affected by Huntington's disease. Participants, including gene carriers, people with symptoms, and at-risk or unaffected relatives, complete yearly clinical, cognitive, and optional biological assessments. It does not test a drug, but the data and biosamples it gathers power much of today's Huntington's research and help match people to future clinical trials. Many people connect with the research community by joining. Ask an HD clinic near you about taking part.