Gene Therapy for Huntington's Disease

Not currently recruiting at 13 trial locations

Overseen By uniQure

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UniQure Biopharma B.V.

Must be taking: Immunosuppressants

Must not be taking: Experimental agents

Disqualifiers: Suicide risk, Experimental agents, Brain implants, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy, AMT-130, to assess its safety and effectiveness for individuals with early signs of Huntington’s disease. Huntington’s disease is a brain disorder affecting movement, thinking, and emotions. Participants will receive varying doses of the therapy to determine its optimal use. Individuals with early symptoms of Huntington’s, confirmed by a genetic test, and stable medication routines may be suitable for this study. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in Huntington’s disease therapy.

Will I have to stop taking my current medications?

The trial requires that all medications for Huntington's disease symptoms must be stable for 3 months before joining the study, meaning you should not change your current medications during this time.

Will I have to stop taking my current medications?

The trial requires that all medications for Huntington's disease symptoms must be stable for 3 months before joining the study, meaning you should not change your current medications during this time.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AMT-130, a gene therapy for Huntington's Disease, is generally well-tolerated. Studies have found that both low and high doses of AMT-130 have manageable safety profiles. Importantly, as of mid-2025, no new serious side effects related to the drug have emerged. This suggests that the treatment is safe for humans, at least in the short term. These findings offer reassurance about the treatment's safety for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for Huntington’s Disease, which mainly address symptoms and include medications like tetrabenazine and antipsychotic drugs, AMT-130 offers a novel approach by targeting the root cause. AMT-130 uses a gene therapy technique involving AAV5-miHTT, which aims to reduce the production of the mutant huntingtin protein that drives the disease. This is significant because it could potentially slow down or halt the progression of the disease, rather than just managing symptoms. Researchers are excited because this could lead to a more effective long-term solution for those affected by Huntington’s Disease.

What evidence suggests that this trial's treatments could be effective for Huntington's Disease?

Research has shown that AMT-130, a type of gene therapy, may help treat Huntington's Disease by reducing the production of the protein huntingtin. In this trial, participants will receive either a low or high dose of AMT-130 or undergo imitation (sham) surgery as a comparator. Specifically, earlier studies found that people who received a high dose of AMT-130 experienced a 75% reduction in disease progression over three years. The treatment was generally well-tolerated, with no new serious side effects reported. Additionally, studies in animals demonstrated that AMT-130 lowers huntingtin levels and reduces signs of the disease. These findings suggest that AMT-130 could help manage symptoms of Huntington's Disease. ^{1 2 4 6 7}

Who Is on the Research Team?

David H. Margolin, MD, PhD

Principal Investigator

uniQure, Inc.

Are You a Good Fit for This Trial?

Adults aged 25-65 with early manifest Huntington's Disease (HD), stable on medications for at least 3 months, and not involved in other trials or brain surgeries. They must have specific gene markers, be able to follow the study plan, and use effective birth control if applicable. Exclusions include certain medical conditions, recent major surgery, abnormal lab values, implanted devices in the brain, MRI contraindications, cancer within 5 years (except some skin cancers), or recent COVID-19 infection.

Inclusion Criteria

I am between 25 and 65 years old.

Your brain MRI must show that certain areas called the putamen and caudate are a certain size.

My medications for HD symptoms have been stable for 3 months.

Exclusion Criteria

Your blood tests show: a. High levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) b. High levels of total bilirubin or alkaline phosphatase (ALP) c. High levels of creatinine d. Low platelet count e. Abnormal prothrombin time (PT) or partial thromboplastin time (PTT)

I am not allowed to have a lumbar puncture due to medical reasons.

I haven't had cancer in the last 5 years, except for certain skin cancers or cervical cancer that was treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either high or low dose AMT-130 with pre and post-operative immunosuppressant therapies

12 months

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

Periodic follow-up visits

Optional Extended Follow-Up

Cohort 2 Sham participants who do not cross over to receive AMT-130 treatment will be followed for an additional 2 years

24 months

What Are the Treatments Tested in This Trial?

Interventions

• AMT-130
• Imitation (sham) surgery

Trial Overview

The trial is testing AMT-130 in patients with early HD to check its safety and effectiveness. It involves a randomized comparison between two doses of intra-striatal rAAV5-miHTT gene therapy versus imitation (sham) surgery. Participants are assigned randomly to receive either a high or low dose of the treatment.

How Is the Trial Designed?

Group I: Cohort 4 Experimental Treatment 1 Intervention

High dose rAAV5-miHTT (6x10\^13 gc/subject).

Group II: Cohort 3 Experimental Treatment 1 Intervention

Low dose rAAV5-miHTT (6x10\^12 gc/subject). High dose rAAV5-miHTT (6x10\^13 gc/subject).

Group III: Cohort 2 Experimental Treatment 1 Intervention

High dose rAAV5-miHTT (6x10\^13 gc/subject).

Group IV: Cohort 1 Experimental Treatment 1 Intervention

Low dose rAAV5-miHTT (6x10\^12 gc/subject). Note: gc = genome copies

Group V: Cohorts 1, 2 Placebo Group 1 Intervention

Imitation (sham) surgery

AMT-130 is already approved in United States, European Union for the following indications:

Approved in United States as AMT-130 for:

• None approved; under investigation for Huntington's disease

Approved in European Union as AMT-130 for:

• None approved; under investigation for Huntington's disease

Who Is Running the Clinical Trial?

UniQure Biopharma B.V.

Lead Sponsor

Trials

12

Recruited

260+

Published Research Related to This Trial

A 36-year-old woman with the akinetic-rigid variant of Huntington's disease showed significant improvement in parkinsonism, bradykinesia, and dystonia after 5 days of intravenous amantadine treatment, as measured by the Unified Huntington's Disease Rating Scale.

This case suggests that amantadine, which increases dopamine levels in the brain, may be beneficial for patients with this specific variant of Huntington's disease, marking a novel application of the drug beyond its typical use in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine in the akinetic-rigid variant of Huntington's disease. Magnet, MK., Bonelli, RM., Kapfhammer, HP.[2013]

Primary T cells and hybridomas can be effectively modified to deliver immunoregulatory proteins directly to inflamed tissues in autoimmune diseases, showing promise for targeted therapy.

In experimental models of autoimmune diseases like multiple sclerosis and collagen-induced arthritis, T cells engineered to express specific cytokines (like IL-4 and IL-12p40) demonstrated the ability to either prevent or treat disease symptoms, highlighting their potential for cell-based gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cellular gene therapy of autoimmune disease. Slavin, AJ., Tarner, IH., Nakajima, A., et al.[2019]

Genetically engineered T cells, particularly chimeric antigen receptor (CAR) T cells, show promise in treating central nervous system (CNS) conditions like lymphoma and brain tumors, offering better efficacy and tissue penetration compared to traditional antibody therapies.

Current clinical trials are exploring engineered T-cell therapies for autoimmune diseases like multiple sclerosis, focusing on their safety and ability to selectively eliminate harmful B cells or regulate inflammation, which could provide new treatment options for conditions with limited therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic Cell-Based Immunotherapies for Neurologic Diseases. von Baumgarten, L., Stauss, HJ., Lünemann, JD.[2023]

A new eukaryotic expression vector for the TRAIL gene was successfully constructed using the hTERT promoter, which showed effective expression in ovarian cancer cells (SKOV3).

Transfection of this vector into SKOV3 cells significantly inhibited cell growth and induced apoptosis, suggesting that targeting the hTERT promoter could be a promising strategy for treating ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction of TRAIL gene eukaryotic expression vector modulated by hTERT gene core promoter and its effect on apoptosis of ovarian cancer cells]. Li, HM., Song, TB., Yu, YC., et al.[2012]

In a preclinical study using an acute Huntington's disease rat model, AAV5-delivered microRNAs effectively suppressed mutant huntingtin (HTT) expression, preventing the formation of harmful aggregates and neuronal dysfunction.

The gene therapy approach showed no activation of immune responses, indicating a favorable safety profile, which supports further development of RNA interference-based treatments for Huntington's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease. Miniarikova, J., Zimmer, V., Martier, R., et al.[2020]

Adoptive immunotherapy using myelin basic protein-specific CD4+ T cells that express the IL-12 p40 subunit significantly reduced clinical symptoms in a mouse model of multiple sclerosis, indicating a targeted approach to modulate autoimmune responses.

The study demonstrated that these transduced T cells effectively trafficked to the central nervous system and maintained long-term expression of the therapeutic gene, suggesting a promising method for localized treatment of autoimmune diseases without the toxicity associated with systemic cytokine delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit. Costa, GL., Sandora, MR., Nakajima, A., et al.[2019]

AAV5-miHTT, a therapy targeting mutant Huntingtin protein for Huntington disease, showed an excellent safety profile in non-human primates and rats, with no significant neurological symptoms observed during a 6-month study.

The use of real-time MRI for precise delivery of AAV5-miHTT to the brain was successful, demonstrating effective distribution of the therapy in areas affected by Huntington disease, supporting its advancement to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology. Spronck, EA., Vallès, A., Lampen, MH., et al.[2021]

High-capacity adenoviral (HC-Ad) vectors successfully delivered both truncated and full-length mutant huntingtin (htt) proteins in vitro and in vivo, leading to the formation of htt inclusions, which are markers of Huntington's disease pathology.

The study found that truncated mutant htt formed inclusions primarily in the cell nuclei, while full-length mutant htt inclusions localized to the cytoplasm, highlighting differences in their behavior and potential implications for understanding Huntington's disease mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inducing huntingtin inclusion formation in primary neuronal cell culture and in vivo by high-capacity adenoviral vectors expressing truncated and full-length huntingtin with polyglutamine expansion. Huang, B., Schiefer, J., Sass, C., et al.[2016]

Current treatments for autoimmune diseases are largely nonspecific and can lead to serious side effects, highlighting the need for targeted therapies.

Gene therapy using autoantigen-specific T cells to deliver immunoregulatory molecules locally shows promise in animal models, as demonstrated by the effects of transduced T cell hybridomas in a murine model of multiple sclerosis, suggesting a potential new approach to treating autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local delivery of cytokines by retrovirally transduced antigen-specific TCR+ hybridoma cells in experimental autoimmune encephalomyelitis. Dal Canto, RA., Costa, G., Shaw, MD., et al.[2012]

A recent phase 1/2a study involving 46 adults with early Huntington disease showed that the antisense oligonucleotide RG6042, which partially reduces huntingtin protein levels, was generally safe and well tolerated over four monthly doses.

Evidence from both human case studies and mouse models suggests that reducing variant huntingtin protein can improve symptoms and may not pose significant risks, indicating a positive risk-benefit profile for therapies targeting huntingtin levels in Huntington disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks. Leavitt, BR., Kordasiewicz, HB., Schobel, SA.[2021]

There are several promising disease-modifying therapies for Huntington's disease (HD) currently in human clinical trials, including gene therapies and RNA modulation, which aim to address the underlying causes of the disease rather than just its symptoms.

The pathogenesis of HD involves complex toxic pathways stemming from the mutant huntingtin gene, highlighting the need for innovative treatments that target these mechanisms to potentially alter the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Huntington's Disease: New Frontiers in Therapeutics. Pan, L., Feigin, A.[2021]

Huntington's disease (HD) currently has no cure, but various medications and non-drug treatments can help manage symptoms like chorea and cognitive decline, with new therapies targeting the underlying cause of the disease in clinical trials.

Emerging treatments, particularly antisense oligonucleotide (ASO) therapies, aim to lower levels of the harmful mutant huntingtin protein (mHTT), and other innovative approaches like RNA interference and CRISPR are also being explored for their potential to treat HD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Possible Future Therapeutic Options for Huntington's Disease. Ferguson, MW., Kennedy, CJ., Palpagama, TH., et al.[2022]

New therapeutic approaches for Huntington's disease aim to directly target the HTT gene mutation, with methods like CRISPR-Cas9 and zinc-finger transcription repressors potentially preventing the disease's harmful effects at the DNA level.

Antisense oligonucleotides (ASOs) have been shown to safely reduce levels of the mutant huntingtin protein in patients' brains, and they are currently in late-stage clinical trials, indicating promising progress in modifying the disease's course.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic strategies for Huntington's disease. Estevez-Fraga, C., Flower, MD., Tabrizi, SJ.[2021]

Huntington's disease is caused by a genetic mutation in the huntingtin gene, leading to symptoms like chorea and psychiatric disorders, and various therapeutic strategies are being explored, including symptomatic treatments and advanced molecular therapies.

While many modern therapeutic strategies, such as targeting the mutant huntingtin protein and enhancing autophagic clearance, are still in experimental stages, the identification of the causal gene has opened new avenues for potential treatments that were previously unimaginable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Strategies in Huntington's Disease. Kanazawa, I.[2021]

Transgenic and knock-in animal models of Huntington's disease (HD) are crucial for preclinical evaluation of treatment targets, leading to several promising approaches that have progressed to clinical trials.

Ongoing biomarker studies like TRACK-HD and PREDICT-HD are exploring new outcome measures, such as volumetric imaging and quantitative motor assessments, which may enhance the reliability and sensitivity of clinical trials for HD, potentially speeding up the development of effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trials in Huntington's disease: Interventions in early clinical development and newer methodological approaches. Sampaio, C., Borowsky, B., Reilmann, R.[2022]

Citations

1.

uniqure.gcs-web.com

uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-positive-topline-results-pivotal-phase-iii

uniQure Announces Positive Topline Results from Pivotal ...

... ~ Pivotal study met primary endpoint; high-dose AMT-130 demonstrated statistically significant 75% disease slowing at 36 months as ...

2.

eurohuntington.org

eurohuntington.org/2025/10/10/recent-results-for-amt-130-a-step-towards-treatments-that-could-slow-huntingtons-disease/

Recent results for AMT-130: a step towards treatments ...

AMT-130 is an experimental gene therapy that was designed to reduce the amount of huntingtin protein produced by cells. Unlike other treatments ...

3.

en.hdbuzz.net

en.hdbuzz.net/additional-clarity-what-we-know-4-weeks-after-the-uniqure-news/

What We Know 4 Weeks After the uniQure News

According to uniQure's update, trial participants receiving the high dose of AMT-130 who have been followed for 3 years have experienced a 75% ...

4.

uniqure.com

uniqure.com/programs-pipeline/huntingtons-disease

Huntington's Disease | Programs & Pipeline

AMT-130 was generally well-tolerated, with a manageable safety profile at both doses. As of June 30, 2025, no new drug-related serious adverse events have been ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04120493

Safety and Proof-of-Concept (POC) Study With AMT-130 in ...

Preclinical studies have shown that AMT-130 lowers huntingtin protein and is associated with decreased progression of Huntington's Disease signs in animal ...

6.

neurologyadvisor.com

neurologyadvisor.com/news/gene-therapy-slows-huntington-disease-progression-in-pivotal-trial/

Gene Therapy Slows Huntington Disease Progression in ...

Interim results showed high dose AMT-130 slowed disease progression by 75%, as measured by the composite Unified Huntington's Disease Rating ...

7.

hdsa.org

hdsa.org/blog/uniqure-announces-positive-safety-data-in-study-of-amt-130/

uniQure announces positive safety data in study of AMT-130

The press release indicated that the drug has been well-tolerated with no significant safety concerns observed after the first year of follow-up. On average, ...