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

Open to people ages 25-65

1. Able and willing to provide written informed consent prior to the study and study-related procedure
2. Subjects 25 to 65 years of age of both sexes
3. Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic classification 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
4. HTT gene expansion testing with the presence of ≥40 CAG repeats
5. Striatal MRI volume requirements per hemisphere: Putamen ≥2.5 cm3 (per side); Caudate ≥2.0 cm3 (per side)
6. 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
7. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol
8. All female subjects 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.

1. Evidence of suicide risk
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) 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 (ASO), cell transplantation or any other experimental brain surgery.
6. Any contraindication to 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 lumbar puncture 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, infection, or other significant concurrent medical

   condition or medications that could confound clinical and laboratory evaluations or could affect a subject's safety or their ability to undergo the neurosurgical 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. 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
   1. Partial thromboplastin time (PTT) >1.2 × ULN
      1. Known documented COVID-19 requiring hospitalization, with a history of symptomatic diabetes or immune compromise, or with residual respiratory or cardiac symptom associated with COVID-19