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

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.