Gene Therapy for Huntington's Disease

Recruiting at 13 trial locations

Overseen By uniQure 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

37 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment AMT-130 for Huntington's Disease?

The research highlights that new therapies for Huntington's Disease, including those targeting the disease at its genetic origin, are in clinical trials. These therapies aim to lower levels of the mutant huntingtin protein, which is a promising approach for treating the disease. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment AMT-130 for Huntington's Disease?

The research highlights that new therapies for Huntington's Disease are being developed to target the disease at its origin, such as lowering the levels of the mutant huntingtin protein. While specific data on AMT-130 is not provided, similar approaches like RNA interference therapies are being explored in clinical trials, suggesting a promising direction for treatments like AMT-130. ^{1 2 3 4 5}

Is gene therapy for Huntington's disease safe for humans?

Research on gene therapy for Huntington's disease, specifically using AAV5-miHTT, shows it is generally safe and well tolerated in animal studies, including non-human primates and rodents. Additionally, a related therapy, RG6042, was found to be safe in a small human trial, suggesting a positive safety profile for these types of treatments. ^{6 7 8 9 10}

Is gene therapy for Huntington's Disease generally safe in humans?

Research on gene therapy for Huntington's Disease, specifically using AAV5-miHTT, shows it is generally safe and well-tolerated in animal studies, with no significant safety concerns observed. Additionally, a related therapy, RG6042, was found to be generally safe in a small human study, suggesting a positive safety profile for these types of treatments. ^{6 7 8 9 10}

How is the treatment AMT-130 for Huntington's Disease different from other treatments?

AMT-130 is a gene therapy that targets the root cause of Huntington's Disease by delivering genetic material directly to the brain to reduce the production of the harmful huntingtin protein, which is unique compared to traditional treatments that mainly address symptoms. ^{11 12 13 14 15}

How is the treatment AMT-130 for Huntington's Disease different from other treatments?

AMT-130 is a gene therapy that targets the root cause of Huntington's Disease by delivering genetic material to modify the expression of the huntingtin gene, which is not addressed by traditional treatments that mainly focus on managing symptoms. ^{11 12 13 14 15}

What is the purpose of this trial?

This trial tests AMT-130, a one-time gene therapy, in patients with early-stage Huntington's Disease. The treatment aims to lower a harmful brain protein to slow down the disease's progression. AMT-130 has shown promise in early research.

Research Team

David Margolin, MD, PhD

Principal Investigator

UniQure Biopharma B.V.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Cohort 3 Experimental Treatment 1 Intervention

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

Group II: Cohort 2 Experimental Treatment 1 Intervention

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

Group III: Cohort 1 Experimental Treatment 1 Intervention

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

Group IV: 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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Huntington's Disease: New Frontiers in Therapeutics. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Current and Possible Future Therapeutic Options for Huntington's Disease. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Therapeutic strategies for Huntington's disease. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

Therapeutic Strategies in Huntington's Disease. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical trials in Huntington's disease: Interventions in early clinical development and newer methodological approaches. [2022]

6. Switzerland 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. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks. [2021]

8. England 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. [2020]

9. England 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. [2016]

10. United States pubmed.ncbi.nlm.nih.gov

Amantadine in the akinetic-rigid variant of Huntington's disease. [2013]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Adoptive cellular gene therapy of autoimmune disease. [2019]

12. France pubmed.ncbi.nlm.nih.gov

Local delivery of cytokines by retrovirally transduced antigen-specific TCR+ hybridoma cells in experimental autoimmune encephalomyelitis. [2012]

13. United States pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit. [2019]

14. United States pubmed.ncbi.nlm.nih.gov

Synthetic Cell-Based Immunotherapies for Neurologic Diseases. [2023]

15. China 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]. [2012]