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

Inclusion Criteria:

• Able and willing to provide written informed consent prior to the study andstudy-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 DCLof 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 DCLof 4 or a DCL of 3 with either a positive "Yes" response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) orDSM5 criteria for cognitive disorder (Movement Disorder Society Task Forcecriteria).

• 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 cognitivesymptoms) must be stable for 3 months prior to Screening with no change in clinicalsymptoms requiring change in medication prior to anticipated administrationprocedure

• Able and willing to comply with all procedures and the study visit schedule asoutlined in the protocol

• All female participants of childbearing potential (FOCP) must have a negative serumpregnancy test at Screening, (and Visit 1A, as appropriate), a negative pregnancyurine dipstick at Baseline, and not be breastfeeding. All FOCPs and sexually maturemales 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 toScreening or anytime over the duration of this study.

• Participation in an investigational trial or investigational paradigm (such asexercise/physical activity, cognitive therapy, brain stimulation) within 60 daysprior to Screening or anytime over the duration of this study.

• Presence of an implanted deep brain stimulation device, ventriculoperitoneal orother 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 otherexperimental 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-130or 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 carcinomaof the skin or carcinoma in situ of the cervix that has been successfully treated

• Hospitalization for any major medical or surgical procedure involving generalanesthesia within 12 weeks of Screening or planned during the study

• Current or recurrent disease, (including pre-existing cardiovascular or pulmonaryconditions) infection, or other significant concurrent medical condition ormedications that could confound clinical and laboratory evaluations or could affecta participant's safety or their ability to undergo the neurosurgical procedure orcomply with the procedures and study visit schedule

• Known or suspected intolerance or hypersensitivity to the investigationalproduct(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. Alanineaminotransferase (ALT) >2 × upper limit of normal (ULN) b. Aspartateaminotransferase (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.Prothrombintime (PT) >1.2 × ULN h. Partial thromboplastin time (PTT) >1.2 × ULN

• Known allergy, sensitivity, or other contraindication to medications in theimmunosuppression 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 isavailable, may receive treatment after recovery.

• Cohort 4 ONLY: Inability to establish a safe trajectory to administer AMT-130 to thetarget structures, as assessed by neuroimaging.