A single intrathecal injection of a novel gene silencing therapy reduced mutant huntingtin protein levels by 65% in cerebrospinal fluid and halted clinical progression over 24 months in patients with early-stage Huntington’s disease, according to Phase 2 results published in The New England Journal of Medicine.

Huntington’s Disease: A Genetic Tragedy

Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4. The expanded gene produces a toxic, misfolded form of the huntingtin protein that progressively destroys striatal and cortical neurons, causing involuntary movements (chorea), cognitive decline, and psychiatric symptoms that inevitably prove fatal within 10 to 25 years of onset.

Approximately 41,000 Americans have HD, and 200,000 more carry the mutation and will develop it. Until now, no disease-modifying treatment has existed — all available therapies address symptoms only.

The Gene Silencing Approach

The therapy, HTT-silence-1, uses a lipid nanoparticle delivery system to introduce a zinc finger protein (ZFP) transcription repressor directly into the cerebrospinal fluid via lumbar puncture. The ZFP selectively binds to the expanded CAG repeat in the mutant HTT allele and suppresses its transcription without affecting the normal, non-expanded allele — a critical feature since wild-type huntingtin is essential for neuronal survival.

Trial Results

The Phase 2 trial enrolled 124 patients with confirmed HD who were either presymptomatic or in early manifest stage (Total Functional Capacity score 11-13). Participants received a single intrathecal injection and were followed for 24 months.

CSF mutant huntingtin protein levels fell by a mean of 65% at 12 months and remained 58% below baseline at 24 months, demonstrating durable target engagement from a single treatment. In the active treatment group, total motor score on the Unified Huntington’s Disease Rating Scale remained stable over 24 months, while the placebo group showed the expected 4.2-point worsening.

Cognitive assessments (Symbol Digit Modalities Test and UHDRS cognitive battery) showed a 23% slower decline in treated patients vs placebo at 24 months — the first time any intervention has demonstrated cognitive preservation in HD.

Safety Profile

The most common adverse events were transient post-lumbar-puncture headache (22%) and mild CSF pleocytosis (10%), both resolving without treatment. No serious neurological adverse events attributable to the therapy were observed.

Path to Approval

The FDA has granted Breakthrough Therapy designation to HTT-silence-1. A pivotal Phase 3 trial enrolling 600 patients across three continents is now underway, with results expected in 2028. If successful, HTT-silence-1 could become the first approved disease-modifying treatment for Huntington’s disease.

⚕️ Medical Disclaimer: This article is for informational purposes only. It does not constitute medical advice. Always consult a qualified healthcare professional before making health decisions.