Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease

A Phase 1/2, Randomized, Double-Blind, Sham Control and Open-Label Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington's Disease

This is the first study of AMT-130 in patients with early manifest HD and is designed to establish safety and proof-of-concept (PoC). CT-AMT-130-01 is a Phase 1/2, multicenter, first-in-human (FIH) study. The first three cohorts of the study have completed enrollment, including the randomized, double-blind, sham-controlled cohorts. Cohort 4 is open-label.

Cohort 4 participants will receive high dose AMT-130.

Study Overview

• Status: Active, not recruiting
• Conditions: Huntington's Disease
• Intervention / Treatment: Genetic: intra-striatal rAAV5-miHTT; Other: Imitation (sham) surgery

Detailed Description

AMT-130 is an investigational, single administration gene therapy intended to modify the disease course for HD. Preclinical studies have shown that AMT-130 lowers huntingtin protein and is associated with decreased progression of Huntington's Disease signs in animal models.

Cohort 1, 2, and 3 evaluated low dose and high dose AMT-130.

Cohort 4 will further evaluate the safety of high dose AMT-130 in participants with low striatal volume. All participants in Cohort 4 will receive high dose AMT-130 and will receive pre- and post-operative dexamethasone.

Cohorts 1 and 2 participants continue follow-up visits through 6 years after receipt of AMT-130. Cohorts 3 and 4 participants continue follow-up visits through 5 years after receipt of AMT-130.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0111
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona (Surgical Site Only)
  • California
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Colorado
    • Englewood, Colorado, United States, 80113
      • CenExel Rocky Mountain Clinical Research
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan Department of Neurology
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University VCU School of Medicine, Department of Neurology
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able and willing to provide written informed consent prior to the study and study-related procedure
• Participants 25 to 65 years of age of both sexes
• Cohorts 1, 2, & 4: Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic confidence level (DCL) of 4 OR a DCL of 3 if the subject either meets the definition of multidimensional manifest HD (UHDRS question 80) or has cognitive symptoms
• 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).
• HTT gene expansion testing with the presence of ≥40 CAG repeats
• Striatal MRI volume requirements per hemisphere:
• Cohorts 1, 2, & 3: Putamen ≥2.5 cm^3 (per side); Caudate ≥2.0 cm^3 (per side)
• Cohort 4: Putamen <2.5 cm^3 (on either side); Caudate <2.0 cm^3 (on either side)
• All HD concomitant medications (addressing motor, behavioral, and cognitive symptoms) must be stable for 3 months prior to Screening with no change in clinical symptoms requiring change in medication prior to anticipated administration procedure
• Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol
• All female participants of childbearing potential (FOCP) must have a negative serum pregnancy test at Screening, (and Visit 1A, as appropriate), a negative pregnancy urine dipstick at Baseline, and not be breastfeeding. All FOCPs and sexually mature males must be compliant with a highly effective birth control method.

Exclusion Criteria:

• Evidence of suicide risk
• Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.
• Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or anytime over the duration of this study.
• Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter
• Any history of gene therapy, RNA or DNA targeted HD specific investigational agents, such as antisense oligonucleotides (ASOs), cell transplantation or any other experimental brain surgery.
• Any contraindication to 3.0 Tesla MRI as per local guidelines
• Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder
• 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
• Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
• Current or recurrent disease, (including pre-existing cardiovascular or pulmonary conditions) infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a participant's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule
• Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients
• Any known allergy to gadoteridol (ProHance)
• Screening laboratory values (as measured by the central laboratory): a. Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) b. Aspartate aminotransferase (AST) >2 × ULN c. Total bilirubin >2 × ULN d. Alkaline phosphatase (ALP) >2 × ULN e. Creatinine >1.5 × ULN f. Platelet count <100,000/mm3g.Prothrombin time (PT) >1.2 × ULN h. Partial thromboplastin time (PTT) >1.2 × ULN
• Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.
• Any participant with an active infection (e.g., coronavirus disease 2019 [COVID-19]) at Screening or at the time of treatment that requires medical intervention. Participants may rescreen, or if screened eligible and an open surgical slot is available, may receive treatment after recovery.
• Cohort 4 ONLY: Inability to establish a safe trajectory to administer AMT-130 to the target structures, as assessed by neuroimaging.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 2; High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130
Sham Comparator: Cohorts 1, 2; Imitation (sham) surgery	Other: Imitation (sham) surgery; Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull
Experimental: Cohort 3; Low dose rAAV5-miHTT (6x10^12 gc/subject). High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130
Experimental: Cohort 1; Low dose rAAV5-miHTT (6x10^12 gc/subject). Note: gc = genome copies	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130
Experimental: Cohort 4; High dose rAAV5-miHTT (6x10^13 gc/subject).	Genetic: intra-striatal rAAV5-miHTT; One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain; Other Names: AMT-130

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and type of Adverse Events (AE)	Safety will be assessed by adverse events (AEs) related to clinical safety laboratory tests, vital signs, electrocardiograms (ECGs), neurological and physical examinations, rAAV5 vector shedding, immunogenicity response (Cohorts 1, 2 & 3), suicidality risk [Columbia-Suicide Severity Rating Scale [C-SSRS)], changes in global cognitive functioning [Montreal Cognitive Assessment Scale (MoCA)] and MRI measures of edema, inflammation, volume loss and structural changes.	12 months (Cohorts 1 & 2) and 12 months (Cohort 3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of persistence of AMT-130 in the brain	Change over time in levels of AMT-130-derived Vector DNA Expression in the Cerebrospinal Fluid (CSF)	Collected for duration of study through month 72 (Cohorts 1 & 2) and through month 16 (Cohorts 3 & 4)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CSF Mutant Protein (fM)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 72
CSF/Serum Neurofilament Light Chain (pg/mL)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 72
Unified Huntington Disease Rating Scale (UHDRS)	The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities.	Collected for duration of study through month 72
Quantitative Motor (Q-Motor) Testing	Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 72 (Cohorts 1, 2 & 3)
Magnetic Resonance Imaging (MRI)	MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures.	Collected for duration of study through month 72
Neuro-QoL Measures	The Neuro-QoL is a brief, reliable, valid, standardized set of patient reported, Health Related Quality of Life (HRQoL) measures for people living with neurological conditions.	Collected for duration of study through month 72

Collaborators and Investigators

• Sponsor: UniQure Biopharma B.V.
• Investigators: Study Director: David H. Margolin, MD, PhD, uniQure, Inc.

Publications and helpful links

General Publications

• Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: April 2020. J Huntingtons Dis. 2020;9(2):185-197. doi: 10.3233/JHD-200002.
• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006.
• Pala M, Yilmaz SG. Circular RNAs, miRNAs, and Exosomes: Their Roles and Importance in Amyloid-Beta and Tau Pathologies in Alzheimer's Disease. Neural Plast. 2025 Apr 8;2025:9581369. doi: 10.1155/np/9581369. eCollection 2025.
• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017.

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2019
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Estimated): October 21, 2025
• Last Update Submitted That Met QC Criteria: October 17, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Gene therapy; Viral vector; AAV (adeno-associated virus); serotype 5 AAV (adeno-associated virus); serotype 5; miHTT; muHTT; Huntington's Disease (HD)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Huntington Disease; salicylhydroxamic acid; Surgical Procedures, Operative
• Other Study ID Numbers: CT-AMT-130-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No