intra-striatal rAAV5-miHTT: One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Study summary
This is the second study of AMT-130 in patients with early manifest HD and is designed as part of an integrated two-study phase I/II program under a single data safety monitoring board (DSMB) with staggered enrollment based upon continued demonstration of safety of AMT-130 administration.
Cohort 3 participants will receive either high or low dose (1:1 randomization). Participants enrolled in Cohort 3 will also receive an immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab.
Eligibility
Sex
ALL
Min age
25 Years
Max age
65 Years
Healthy volunteers
No
Inclusion Criteria:
1. Able and willing to provide written informed consent prior to the study and study-related procedure.
2. Male and female participants 25-65 years of age.
3. Cohorts 1 \& 2:
1. a DCL of 4 OR
2. a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).
4. Cohort 3:
1. a DCL of 4 OR
2. a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).
5. HTT gene expansion testing with the presence of ≥40 CAG repeats (confirmed by genetic testing at central laboratory).
6. Striatal MRI volume requirements per hemisphere:
1. Putamen ≥2.5 cm3 (per side)
2. Caudate ≥2.0 cm3 (per side)
7. 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.
8. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol.
9. All female participants of childbearing potential (FCOP) must have 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 highly effective birth control method as outlined in Section 4.5.
Exclusion Criteria:
1. Evidence of suicide risk, defined as:
1. Suicide attempt within 1 year prior to Screening (Visit 1/1A)
2. Suicidal ideation as defined by a positive response to question 5 on Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Section within 60 days prior to Screening (Visit 1/1A)
3. Significant risk of suicide as judged by the Investigator
2. Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.
3. Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc.) within 60 days prior to Screening or anytime over the duration of this study.
4. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter
5. 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.
6. Any contraindication to lumbar puncture or 3.0 Tesla MRI as per local guidelines.
7. Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder.
8. Any contraindication to 3.0 Tesla MRI as per local guidelines
9. 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.
10. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study.
11. 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 a neurosurgical procedure (10+ hour surgical procedure) or comply with the procedures and study visit schedule.
12. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients.
13. Any known allergy to gadoteridol (ProHance).
14. Screening laboratory values (as measured by the central laboratory):
1. Alanine aminotransferase (ALT) \>2 × upper limit of normal (ULN)
2. Aspartate aminotransferase (AST) \>2 × ULN
3. Total bilirubin \>2 × ULN
4. Alkaline phosphatase (ALP) \>2 × ULN
5. Creatinine \>1.5 × ULN
6. Platelet count \<100,000/mm3
7. Prothrombin time (PT) \>1.2 × ULN
8. Partial thromboplastin time (PTT) \>1.2 × ULN
15. Known immunocompromised status including participants who have undergone organ transplantation or who test positive at Screening for the human immunodeficiency virus (HIV); or who are at risk of pathogen reactivation if immunosuppressed, including participants who test positive at screening for hepatitis C virus antibody (anti-HCV), hepatitis C virus ribonucleic acid (HCV RNA), hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc); or who have history of active tuberculosis or a positive tuberculosis blood test during screening. For participants with an indeterminate tuberculosis blood test result or positive tuberculosis test result, repeat testing is recommended.
16. Known allergy, sensitivity, or other contraindication to immunosuppression regimens in this protocol.
17. 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.
Primary outcome measure(s)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Adverse Events — 6 months Evaluation will be assessed by;
\- Type and incidence of Adverse Events (AEs)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Blood Pressure — 6 months Evaluation will be assessed by;
\- Changes from baseline in blood pressure (mmHg)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Respiratory Rate — 6 months Evaluation will be assessed by;
\- Changes from baseline in respiratory rate (BPM)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Heart Rate — 6 months Evaluation will be assessed by;
\- Changes from baseline in heart rate (BPM)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Electrocardiograms — 6 months Evaluation will be assessed by;
\- Changes from baseline in electrocardiograms (ECGs) for any clinically significant abnormalities or clinically significant worsening. (normal or abnormal)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the neurological examinations — 6 months Evaluation will be assessed by;
\- Changes from baseline in neurological examinations including mental status, cranial nerves, sensory, motor, fine motor, reflexes, and gait (normal or abnormal)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the physical examinations — 6 months Evaluation will be assessed by;
\- Changes from baseline in physical examinations assessed by physical appearance, HEENT, Neck, Chest and Lungs, Cardiovascular, Abdomen, Musculoskeletal, and Genitourinary (normal or abnormal)
Evaluate the safety and tolerability by number of participants with clinically significant changes in laboratory tests - Clinical Chemistry — 6 months Evaluation will be assessed by;
\- Changes from baseline in Clinical Chemistry laboratory tests with clinical significance.
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinically significant laboratory tests - hematology — 6 months Evaluation will be assessed by;
\- Changes from baseline in hematology laboratory tests with clinical significance.
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinical significant laboratory tests - urinalysis — 6 months Evaluation will be assessed by;
\- Change from baseline in routine urinalysis test with clinical significance.
Evaluate the safety and tolerability o by number of participants with clinical significant changes in cerebrospinal fluid (CSF) analysis — 6 months Evaluation will be assessed by;
\- Change from baseline in CSF analysis with clinical significance.
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by vector shedding — 6 months Evaluation will be assessed by;
\- Change over time in AAV5 vector shedding
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers — 6 months Evaluation will be assessed by;
\- Change over time in microglial activation (YKL-40) (pg/mL)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers — 6 months Evaluation will be assessed by;
\- Change over time in antibodies against AAV5 (g/L)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers — 6 months Evaluation will be assessed by;
\- Change over time in cytokines (pg/mL)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers — 6 months Evaluation will be assessed by;
\- Change over time in ELISpot
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers — 6 months Evaluation will be assessed by;
\- Change over time in astroglial activation (GFAP) (pg/mL)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by cognitive assessment — 6 months Evaluation will be assessed by;
\- Change from baseline to Day 14 and Month 1 in the Montreal Cognitive Assessment (MoCA)
Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with changes in MRI — 6 months Evaluation will be assessed by;
\- Change from baseline will be measured by edema, inflammation, volume loss, and structural changes as measured by the following MRI pulse sequences, T1, T2 and diffusion MRI (dMRI)
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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