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.

The aim of the European study is to build upon the safety demonstrated in the first human dose (FHD) randomized, double blind, sham-controlled sequential dose escalation study (CT-AMT-130-01; clinicaltrials.gov NCT04120493) being conducted in the US and expand the number of patients exposed to the two doses to provide sufficient sample size for comparisons of safety and efficacy. CT-AMT-130-02 is a Phase Ib/II open-label (Cohorts 1 & 2), randomized (Cohort 3 only) sequential multiple dose study that will be conducted in approximately 5 to 8 European HD centers; 2 of these centers will serve as surgical sites. Both studies will share a common set of clinical, safety, imaging, and biomarker evaluations over 5 years of follow-up. The DSMB will evaluate safety and other parameters to enable the staggered treatment of patients within each of the dosing cohorts

Cohort 3 participants will receive either high or low dose AMT-130. Following completion of the Month 36 visit, they will be unblinded to their treatment arm. Cohort 3 will further evaluate the safety and exploratory efficacy data of low or high dose AMT-130. Cohort 3 participants will also receive pre and post-operative immunosuppressant therapies composed of dexamethasone, sirolimus, and rituximab.

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.