Understanding Huntington’s Disease and UCL’s Gene Therapy Idea

Huntington’s disease (HD) is a rare, inherited neurodegenerative disorder that progressively impacts movement, cognition, and behavior. Though it has been recognized for more than a century, our understanding of its genetic basis and molecular pathways has advanced dramatically in recent decades. Still, the search for effective treatments continues, with promising developments on the horizon.

What causes Huntington’s disease? At its core, Huntington’s disease is genetic. It is caused by a mutation in the HTT gene, located on chromosome 4. This mutation involves an abnormal repetition of the DNA sequence CAG, which codes for the amino acid glutamine. Normally, the gene contains up to 35 repeats of CAG; individuals with Huntington’s disease typically have 36 or more repeats. The higher the number of repeats, the earlier symptoms tend to appear. The mutation leads to the production of a toxic form of the huntingtin protein. This altered protein misfolds and accumulates inside neurons, disrupting essential cellular processes such as:

  • Protein clearance mechanisms
  • Mitochondrial function, leading to energy deficits
  • Transcription regulation, interfering with gene expression
  • Synaptic communication, impairing signaling between neurons

The ultimate result is progressive neuronal death, especially in the basal ganglia and cerebral cortex—brain regions critical for movement control, memory, and personality. Huntington’s disease usually develops in mid-adulthood, though juvenile forms exist. Symptoms gradually worsen over 10–25 years, with three main domains affected:

  1. Motor symptoms: involuntary jerking or writhing movements, muscle rigidity and dystonia, impaired gait, balance, and coordination, difficulties with speech and swallowing
  2. Cognitive Symptoms: problems with planning, organizing, and multitasking, decline in memory and concentration, reduced ability to learn new information
  3. Psychiatric Symptoms: depression and anxiety, irritability and aggression, apathy and social withdrawal

Current Treatments and Latest Advances (Including the Very New Breakthrough)

So far, we covered the existing treatments (symptomatic relief, etc.). But there’s fresh, exciting news: as of September 2025, a clinical trial from University College London (UCL) has reported what might be the first disease-modifying therapy for Huntington’s disease.

It’s a gene therapy. Instead of just treating symptoms, it aims to reduce the production of the mutant huntingtin protein, the toxic version that causes neuronal damage in Huntington’s.

The method: a virus vector (adeno-associated virus, likely, or similar) is engineered to deliver an artificial microRNA into the brain. This microRNA targets the huntingtin mRNA (especially the mutant copy), promoting its degradation or reducing its translation. Thus, less toxic protein is made.

So how it was administered ? The therapy is delivered directly into the brain, more precisely into the striatum on both sides. The striatum is one of the key brain regions most affected in HD (important for movement, among other functions). This requires a neurosurgical procedure (brain surgery). The operation is delicate, because you need to get the therapy into the correct brain tissue, and viruses must be delivered in controlled ways so they don’t cause adverse effects.

Early data (from a Phase I/II trial, high-dose group) suggest that disease progression was slowed by about 75%. That is, patients who got the high dose and were followed for some time showed substantially less worsening compared to what is expected historically in Huntington’s. The high-dose group had 17 patients, of which 12 were followed for 36 months. They showed improvements (or at least markedly less decline) on various clinical and biomarker measures. Biomarkers include things like neurofilament light, a proxy for nerve cell damage—these levels were better than expected. In contrast, the low-dose group did not show clear benefit (or at least, it wasn’t reported yet) in these early reports. This suggests dose matters.

If this holds up, it would be the first therapy shown to modify the course of Huntington’s disease instead of just treating symptoms since it is reducing mutant huntingtin could slow down neuronal death, thereby preserving function (motor, cognitive, behavioral) for longer. However there are some uncertainties as well. Brain surgery has risks. Delivering virus into the brain has potential side-effects (inflammation, immune response, off-target effects). Early reports say it was generally well tolerated, but long-term safety still needs thorough monitoring. Additionally, we saw 36-month follow up in some patients, but Huntington’s is a long game (decades). We need to know how long the benefit persists. Lastly, dose optimization: High dose seems promising; low dose didn’t show significant effect yet. Finding the right dose that maximizes benefit and minimizes risk is key.

Conclusion

This new gene therapy trial marks a turning point in Huntington’s disease research. For the first time, there is credible evidence that we might slow disease progression by targeting the root cause—mutant huntingtin protein—rather than only managing symptoms.

That said, the data are still early. These are initial Phase I/II results: promising, but we need more patients, longer follow-ups, peer-reviewed publications, and confirmation of safety and durability. If all goes well, this could become the first approved disease-modifying treatment for HD.

Bibliography

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