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Huntington’s disease (HD) is a rare but devastating inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the HTT gene. This mutation produces a toxic form of the huntingtin protein, progressively damaging neurons in the striatum—the brain region responsible for movement, cognition, and emotional regulation. Symptoms typically appear in midlife and worsen over one to two decades, culminating in severe physical and cognitive decline.

Despite its genetic clarity, HD has long stood as the archetype of intractable neurodegeneration. A single, well-defined mutation exists, yet decades of research have failed to produce a therapy that meaningfully alters disease progression. Treatments ranging from dopaminergic agents to antisense oligonucleotides (ASOs) have largely provided temporary or symptomatic relief, falling short of the ultimate goal: disease modification. Against this backdrop, the recent Phase I/II data for AMT-130 stand out as potentially transformative, offering hope not only for HD but also for other dominantly inherited neurodegenerative diseases.

What Makes AMT-130 Different

Most prior therapies for HD, such as Roche’s intrathecal antisense oligonucleotide (ASO) tominersen, sought broad distribution across the brain. In practice, coverage was uneven, and despite biomarker improvements, some patients worsened—ultimately halting the program, although it may in future still benefit a subpopulation of patients.

AMT-130 takes a more targeted approach. Developed by uniQure, it uses an AAV5 viral vector to deliver a microRNA that selectively silences mutant huntingtin in the brain regions most affected in HD. Delivered via a one-time neurosurgical infusion, this method is high-risk and irreversible—but it ensures the therapy reaches the disease epicenter. This precision addresses a central challenge in HD therapy: achieving meaningful, localized suppression of the toxic protein.

Early Clinical Results: Slowing Disease Progression

The Phase I/II trial data are striking. Over 30 months, patients receiving high-dose AMT-130 showed:

• ~75% slower functional decline on the composite Unified Huntington’s Disease Rating Scale (cUHDRS; a key tool for tracking Huntington’s disease progression. It assesses motor function, cognitive abilities, behavioral symptoms, and overall functional capacity over time) compared to matched external controls.
• ~60% slower loss of daily living abilities (Total Functional Capacity).
• Favourable trends in cognitive and motor tests, with some outcomes suggesting more than 100% slowing compared to expected decline.
• Biomarker evidence: Levels of neurofilament light chain (NfL)—a marker of neuronal damage—remained reduced or below baseline in treated patients, strengthening the case that AMT-130 is addressing disease biology, not just symptoms.
• Safety outcomes were generally favourable, with most adverse events linked to the surgical procedure rather than the therapy itself.

These results mark the first time any therapy has shown such a profound slowing of HD progression in a controlled setting.

Interpreting the Data

While encouraging, these results come with caveats:

• The trial was small and lacked a randomized placebo group, relying on external historical controls.
• Placebo effects in HD can be substantial, and historical comparators are variable.

What strengthens confidence in AMT-130 is the alignment of clinical and biomarker outcomes. In contrast to tominersen, where biomarkers improved but patients continued to deteriorate, AMT-130 shows both functional preservation and biological stabilization—a first in HD therapy.

Broader Implications for Neurodegenerative Gene Therapy

AMT-130 offers insights that may extend beyond HD:

• Durability vs. reversibility:AAV-mediated therapies are “one-and-done.” If benefits fade or adverse events occur, there is no easy fix.
• Safety trade-offs: Direct neurosurgical delivery avoids repeated dosing but introduces risks such as infection and haemorrhage, limiting scalability.
• Economic and access considerations: Manufacturing AAV vectors is complex and costly, and adding neurosurgical requirements will raise future questions about affordability and global accessibility.

A Template for Other Disorders

AMT-130 may serve as a proof-of-concept for other trinucleotide repeat disorders such as spinocerebellar ataxias, myotonic dystrophy, and Friedreich’s ataxia. In these diseases, a toxic gain-of-function from expanded repeats drives pathology, suggesting that targeted gene silencing could have broad applicability.

Future strategies may combine long-term genetic suppression with small molecules or digital therapeutics to manage residual symptoms—a layered approach for complex neurodegenerative disorders.

Looking Ahead

Regulatory attention is high: AMT-130 has received Breakthrough Therapy and RMAT (Regenerative Medicine Advanced Therapy) designations from the U.S. FDA.

These designations matter. RMAT status is specifically designed to speed up the development of regenerative medicine products, such as cell and gene therapies, for serious or life-threatening conditions. To qualify, a therapy must show early evidence of meaningful clinical benefit. In return, RMAT provides closer FDA guidance, streamlined trial design, and the potential for accelerated approval. Combined with Breakthrough Therapy status, this means regulators recognize AMT-130’s promise and are committed to working closely with uniQure to move it forward efficiently.

uniQure plans a biologics license application (BLA) submission in early 2026. Larger, controlled trials will be critical to confirm long-term efficacy and safety, and regulators will scrutinize the durability of treatment effects.

For the HD community, these findings are more than promising—they represent genuine hope. AMT-130 is the first therapy to show a meaningful slowing of HD progression, raising the possibility that science can alter the course of one of neurology’s most intractable diseases.

If these results hold, AMT-130 may not only redefine the outlook for Huntington’s disease but also open the door for transformative gene therapies across a spectrum of inherited neurodegenerative disorders.