Vinay Prasad, head of the FDA office that regulates gene therapies, has criticized the ways in which the agency has tried to expedite the review of certain genetic medicines. He was also a central figure in the FDA’s request to Sarepta Therapeutics’ to pause distribution of Elevidys, a gene therapy for Duchenne muscular dystrophy.

https://www.biopharmadive.com/news/uniqure-fda-huntingtons-gene-therapy-reversal-approval-application/804516/

Summary

AMT-130 is an investigational gene therapy designed to slow Huntington’s disease progression by using a viral vector to deliver genetic material that reduces the production of the toxic huntingtin protein in brain cells. Clinical trial results to date show a significant slowing of disease progression—around 75% reduced progression at 36 months compared to historical controls—along with improvements in cognitive and motor functions, and biomarker evidence suggesting reduced neuronal injury. The therapy involves a one-time neurosurgical delivery and is generally well tolerated. While AMT-130 is specific to Huntington’s disease, the gene therapy platform raises hope for similar approaches in neurodegenerative diseases like Parkinson’s in the future [1], [2], [3].

What is AMT-130?

AMT-130 is the first gene therapy designed to slow the progression of Huntington’s disease (HD), which is caused by a harmful mutation in the huntingtin gene leading to toxic protein accumulation in brain neurons. Developed by uniQure, AMT-130 works by delivering a benign adeno-associated virus (AAV5 vector) carrying a microRNA sequence directly into the brain regions most affected by HD (the caudate nucleus and putamen). This microRNA suppresses the expression of the mutant huntingtin protein, aiming to reduce its toxic effects on neurons [1].

How is AMT-130 administered?

The treatment involves a one-time neurosurgical procedure lasting 12 to 18 hours, where the vector is infused into targeted regions within the brain under real-time imaging guidance. The delivery is permanent, designed to allow long-lasting gene silencing effects without repeated dosing [3].

Clinical trial results and effectiveness

Phase 1/2 trial data involving 29 early-stage HD patients (split into low- and high-dose groups) compared their outcomes to a matched external control group from a large observational study (Enroll-HD). Key findings at 36 months were:

• A 75% slowing in progression of the composite Unified Huntington’s Disease Rating Scale (cUHDRS), with the treated group's score declining by −0.38 compared to −1.52 in controls.

• A 60% improvement in Total Functional Capacity (TFC), indicating better maintenance of patients' ability to perform daily activities.

• Cognitive tests showed improvements with slower decline in processing speed and reading ability.

• Biomarkers in cerebrospinal fluid showed an ~8.2% reduction in neurofilament light chain (NfL), a marker of neuronal injury, suggesting less ongoing brain damage.

• Early data also suggest reductions in mutant huntingtin protein levels in some patients by about 54%.

• Safety profile was generally favorable, with common adverse events related to the surgical procedure including inflammation and headaches, typically manageable [1], [2], [3].

Limitations and critiques of the AMT-130 data

• The trial was small (only 29 patients), and only 12 patients per dose group have full 36-month data.

• There was no placebo-controlled group; comparisons were made against historical/external matched patients, which can introduce bias.

• Results await peer-reviewed journal publication; current information mainly comes from company press releases and secondary reports.

• The clinical impact of the numerical scale improvements on day-to-day lives is yet to be fully understood.

• The treatment requires invasive brain surgery, which carries risks and limits accessibility.

• Cost, availability, and regulatory approval timelines (potentially US launch in 2026–2027) may further restrict widespread use initially [1], [2].

Relevance of AMT-130 to Parkinson's Disease

While AMT-130’s target is mutant huntingtin protein specific to Huntington’s disease, the platform of using gene therapy to reduce toxic protein production is a promising avenue for other neurodegenerative conditions. Experts have suggested that a similar approach might be adapted in the future to target Parkinson’s disease-related proteins such as alpha-synuclein, potentially modifying the course of Parkinson’s. However, this remains theoretical and under research; no approved gene therapy for PD currently exists [3].

Health Disclaimer

Please remember that AMT-130 is currently investigational and not yet approved for general use. Results are preliminary and come from small studies awaiting full peer-reviewed publication. If you or a loved one is affected by Huntington’s disease or Parkinson’s disease and interested in gene therapies or experimental approaches, you should discuss options extensively with your neurologist or movement disorder specialist.

Sources

1. Gene therapy slows Huntington's disease for first time, clinical trial shows

2. AMT-130 gene therapy achieves 75% slowing of Huntington's disease progression

3. Huntington's disease breakthrough: what to know about the gene therapy

Though AMT-130 is focused on Huntington’s disease, its development marks an important milestone in neurodegenerative disease research with exciting prospects for the future of PD treatment. Advances like these bring hope for more targeted and durable therapies.

Huntington’s was the first genetic disease mapped to a specific chromosome. Yet, despite knowing its root cause for more than 40 years, drugmakers have struggled to create effective therapies for the nerve cell-destroying illness. That track record made UniQure’s data all the more exciting. Its trial found that, among 12 participants who were given a high dose of AMT-130 and followed for three years, signs of disease progression appeared to slow by 75%.

New findings suggest that mutations in a gene called GBA – which are a risk factor for developing Parkinson’s disease (PD) – drive cognitive decline by disrupting how neurons communicate with each other in the brain. Patients living with Parkinson’s can experience cognitive symptoms such as difficulty with concentrating and forgetfulness. Over time, many go on to develop dementia.

In the study, researchers analyzed three types of mouse models. Their experiments showed that the SNCA and GBA-SNCA mutants – the two models that had elevated alpha-synuclein – experienced motor deficits that worsened over time, but GBA mutants did not develop any motor deficits. Cognitive deficits, on the other hand, were associated with GBA mutations.

The findings highlight that PD symptoms are driven by different mechanisms, with motor deficits tightly linked to alpha-synuclein buildup and cognitive deficits caused by GBA mutations. While alpha-synuclein aggregations are a common hallmark of Parkinson’s, there is a growing recognition among neuroscientists that not all cases present with this pathology. Click here to learn more.

Parkinson's disease (PD) research aims to understand the causes, mechanisms, and potential treatments for this neurodegenerative disorder.

Areas of Research:

• Genetics: Identifying genetic mutations that increase the risk of PD.

• Neurobiology: Studying the changes in brain cells and pathways that occur in PD.

• Cell Death: Investigating why dopamine-producing neurons die in PD.

• Oxidative Stress: Examining the role of oxidative damage in the disease process.

• Mitochondrial Dysfunction: Exploring how impaired mitochondrial function contributes to PD.

• Stem Cell Therapy: Using stem cells to replace damaged neurons or to protect existing ones.

• Gene Therapy: Developing genetic interventions to stop or slow the progression of PD.

• Drug Discovery: Identifying and testing new medications to improve symptoms and potentially halt disease progression.

Leading Research Institutions: National Institute of Neurological Disorders and Stroke (NINDS), Parkinson's Foundation, Michael J. Fox Foundation for Parkinson's Research, Harvard Stem Cell Institute, and University of Miami Miller School of Medicine.

A $1.9 million U.S. Department of Defense–funded Phase 2 clinical trial will test SwallowFIT, a targeted exercise program designed to retrain the brain’s ability to control the muscles involved in swallowing — a function often compromised in Parkinson’s disease — in active-duty service members, veterans, or their relatives who have been diagnosed with the disease.

SwallowFIT applies the principles of neuroplasticity (the brain’s ability to adapt and form new connections) to help reorganize the signals sent to the muscles involved in swallowing. Through repeated practice, it strengthens the muscles of the mouth, tongue, and throat while retraining the brain to send clearer signals.

In earlier pilot testing, SwallowFIT helped patients improve their ability to swallow. If the clinical trial succeeds, researchers believe it could pave the way for proactive swallowing therapy to become part of early care for dysphagia. Click here to learn more.