What is the mechanism of action of this treatment?

The most common treatments for Huntington's Disease (HD) focus on reducing the levels of the mutant huntingtin (mHTT) protein, which is responsible for the disease's progression. Gene therapy approaches, such as those studied in the AMT-130 trial, use adeno-associated viruses (AAVs) to deliver microRNAs that specifically target and degrade mHTT mRNA, thereby lowering mHTT protein levels. Similarly, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) work by binding to mHTT mRNA and promoting its degradation or preventing its translation. These treatments are crucial for HD patients as they directly address the root cause of the disease, potentially slowing or halting its progression and improving quality of life.

What side effects are associated with this type of intervention?

Common treatments for Huntington's Disease that are similar to the gene therapy being studied in the AMT-130 trial include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and adeno-associated virus (AAV)-mediated RNA interference. Known side effects of these treatments can include injection site reactions, flu-like symptoms, and potential off-target effects leading to unintended gene silencing. Additionally, there may be risks associated with immune responses to the viral vectors used in gene therapy, such as inflammation or other immune-mediated reactions.

What prior FDA approvals exist?

The provided context does not mention specific FDA-approved treatments for Huntington's Disease, particularly gene therapy. However, AMT-130 is an investigational gene therapy being studied for early manifest Huntington's Disease. Generally, treatments for Huntington's Disease have focused on managing symptoms rather than modifying the disease course. Gene therapy, like AMT-130, represents a novel approach aiming to address the underlying genetic cause of the disease.

What other types of research exist?

Promising novel alternatives to AMT-130 for Huntington's Disease patients in 2024 include antisense oligonucleotides (ASOs) and small RNA therapies. ASOs have been well tolerated in patients with amyotrophic lateral sclerosis and are being adapted for HD. Additionally, small RNAs administered to rodent and nonhuman primate brains have successfully knocked down huntingtin mRNA, showing potential for clinical application. These approaches are expected to be ready for clinical studies in the near future.

← Back to Search

Gene Therapy

Gene Therapy for Huntington's Disease

Phase 1 & 2

Waitlist Available

Led By David Cooper, MD, MBA

Research Sponsored by UniQure Biopharma B.V.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

HTT gene expansion testing with the presence of ≥40 CAG repeats

Cohort 3: Early manifest HD as defined by a UHDRS TFC score of ≥ 11 and EITHER a DCL of 4 or a DCL of 3 with either a positive 'Yes' response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (Movement Disorder Society Task Force criteria)

Must not have

Any contraindication to lumbar puncture as per local guidelines

Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 12 months (cohorts 1 & 2) and 12 months (cohort 3)

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

While specific side effects aren't listed here as it's an initial human trial for AMT-130, potential risks may include reactions related to surgical procedures like infection or bleeding and any unforeseen effects from the gene therapy itself.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

My genetic test shows I have more than 40 CAG repeats in the HTT gene.

Select...

I have early-stage Huntington's disease with specific functional and cognitive scores.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

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

Select...

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

Select...

I haven't been hospitalized for major surgery under general anesthesia in the last 3 months.

Select...

I don't have brain or spinal issues that could affect surgery.

Select...

I have not been in any research studies or trials for the last 60 days.

Select...

I have never had gene therapy or experimental brain surgery for Huntington's disease.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 12 months (cohorts 1 & 2) and 12 months (cohort 3)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~12 months (cohorts 1 & 2) and 12 months (cohort 3)

This trial's timeline: 3 weeks for screening, Varies for treatment, and 12 months (cohorts 1 & 2) and 12 months (cohort 3) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number and type of Adverse Events (AE)

Secondary study objectives

Duration of persistence of AMT-130 in the brain

Other study objectives

CSF Mutant Protein (fM)

CSF/Serum Neurofilament Light Chain (pg/mL)

HDQLIFE Measures

+4 more

Trial Design

4Treatment groups

Experimental Treatment

Placebo Group

Group I: Cohort 3Experimental Treatment1 Intervention

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

Group II: Cohort 2Experimental Treatment1 Intervention

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

Group III: Cohort 1Experimental Treatment1 Intervention

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

Group IV: Cohorts 1, 2Placebo Group1 Intervention

Imitation (sham) surgery

0 / 8Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Huntington's Disease (HD) focus on reducing the levels of the mutant huntingtin (mHTT) protein, which is responsible for the disease's progression. Gene therapy approaches, such as those studied in the AMT-130 trial, use adeno-associated viruses (AAVs) to deliver microRNAs that specifically target and degrade mHTT mRNA, thereby lowering mHTT protein levels. Similarly, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) work by binding to mHTT mRNA and promoting its degradation or preventing its translation. These treatments are crucial for HD patients as they directly address the root cause of the disease, potentially slowing or halting its progression and improving quality of life.

AAV5-miHTT Lowers Huntingtin mRNA and Protein without Off-Target Effects in Patient-Derived Neuronal Cultures and Astrocytes.Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease.Delivering a disease-modifying treatment for Huntington's disease.