A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RG6496 in Huntington's Disease

Inclusion Criteria:

Part 1

• Confirmation of HDGEC status with cytosine-adenine-guanine (CAG) expansion > 39.

• Confirmation of SNP carrier status of the target SNP

• Independence Scale (IS) score of ≥70, total functional capacity (TFC) ≥10, totalmotor score (TMS) >6.

• Ability to read the words "red," "blue," and "green" and be fluent in the languageof the informed consent form (ICF) and the tests used at the study site.

• Ability to walk unassisted.

• Total body weight > 40 kilogram (kg) and body mass index (BMI) within the range 18-32 kilogram per square meter (kg/m^2) (inclusive) at baseline.

• Ability to undergo and tolerate MRI scans.

Part 2

• Completed the post-dose safety follow-up period in the Part 1 of the study.

• In the opinion of the Investigator, the participant has not experienced a worseningin health that precludes their safe continued participation in the study.

Exclusion Criteria:

Part 1

• Concurrent or planned participation in any interventional clinical study, includingcurrent use of an ASO or any HTT-lowering therapy or treatment with investigationaltherapy within 90 days or 5 drug-elimination half-lives, whichever is longer priorto screening

• Pregnant or breastfeeding, or with the intention of becoming pregnant during thestudy or within the timeframe in which contraception is required

• Malignancy within 5 years prior to screening

• Planned brain surgery during the study

• Positive HIV test, hepatitis B surface antigen and hepatitis B surface antigen atscreening

• Active psychosis, confusional state, or violent behavior, including aggression thatcould cause harm to self or others, over the 12 weeks prior to screening.

• Current or previous history of a primary independent psychotic disorder.

• Scoliosis or spinal deformity or surgery making IT injection not feasible in anoutpatient setting

• History of attempted suicide or suicidal ideation with plan (i.e., active suicidalideation) that required hospital visit and/or change in level of care within 12months prior to screening.

Part 2

• Prematurely discontinued from Part 1 for any reason (i.e., before the completion ofthe postdose safety follow-up period of Part 1).

• Pregnant or breastfeeding, or with the intention of becoming pregnant during thestudy or within the timeframe in which contraception is required.

• Concurrent or planned participation in any interventional clinical study, includingcurrent use of an ASO or any HTT-lowering therapy

• Received any active investigational treatment other than RG6496 during or sincecompletion of Part 1 of the study.

• Had confirmed Dose-Limiting Adverse Event (DLAE)(s) in Part 1 of the study.