This is a first-in-human (FIH) study of RG6496 that will assess the safety and tolerability of single-ascending doses of RG6496 administered to huntington's disease gene expansion carriers (HDGECs). The study consists of two parts: Part 1 [single-ascending dose] followed by Part 2 [open-label extension (OLE)].

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, total motor score (TMS) >6.
• Ability to read the words "red," "blue," and "green" and be fluent in the language of 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 worsening in health that precludes their safe continued participation in the study.

Exclusion Criteria:

Part 1

• Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy or treatment with investigational therapy within 90 days or 5 drug-elimination half-lives, whichever is longer prior to screening
• Pregnant or breastfeeding, or with the intention of becoming pregnant during the study 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 at screening
• Active psychosis, confusional state, or violent behavior, including aggression that could 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 an outpatient setting
• History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening.

Part 2

• Prematurely discontinued from Part 1 for any reason (i.e., before the completion of the postdose safety follow-up period of Part 1).
• Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required.
• Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy
• Received any active investigational treatment other than RG6496 during or since completion of Part 1 of the study.
• Had confirmed Dose-Limiting Adverse Event (DLAE)(s) in Part 1 of the study.

Part 1: Investigator & participants will be blinded; Part 2: Open-label