An open-label, adaptive multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of RO7234292 in csf and plasma, and safety and tolerability following intrathecal administration in patients with Huntington's disease.

1. Signed Informed Consent Form.
2. Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form.
3. Manifest HD diagnosis, defined as a Diagnostic Confidence Level (DCL) score
of 4.
4. Independence Scale score of >= 70.
5. Genetically confirmed disease by direct DNA testing with a CAP score > 400
(Zhang et al. 2011), calculated as follows:
CAP = Age x (CAG repeat length - 33.66).
6. Ability to read the words "red", "blue" and "green" in the patient's native
language.
7. Ability to walk unassisted without a cane or walker and move about without a
wheelchair on a daily basis as reviewed at screening and baseline visit. Long
distance use of wheelchairs for convenience (e.g., greater than 50 meters) for
transfer is permitted.
8. Body mass index >= 16 and <= 32 kg/m2; total body weight > 40 kg.
9. Ability to tolerate blood draws and lumbar punctures.
10. Estimated glomerular filtration rate >= 60 mL/min/1.73 m2 (Cockcroft-Gault
formula).
11. Ability and willingness, in the Investigator's judgment, to comply with all
aspects of the protocol including completion of interviews and assessments for
the duration of the study.
12. Stable medical, psychiatric, and neurological status for at least 12 weeks
prior to screening and at the time of enrollment.
13. Signed study companion consent for participation if a study companion is
available and fulfills the following criteria:
- Age >= 18 years.
- Reliable and competent, in the Investigator*s judgement.
- Sufficiently knowledgeable of the patient*s condition to complete study
companion assessments of the patient, and likely to remain sufficiently
knowledgeable throughout the study, in the Investigator*s judgement.
- Able to comment on the study participant*s symptoms and functioning
experience, as required per Appendix 1.
Note: Companions with genetic confirmation of the mutant gene can only
participate if they do not have confirmation of motor symptoms onset and, in
the opinion of the Investigator, do not display any disease symptoms (i.e., the
companion must have a DCL of < 4, as well as no cognitive or behavioral change
that would question the validity of the acquired observer-reported data).
All effort should be made to retain the study companion; however, should this
not be possible, a study companion can be replaced and new consent obtained.
14a. For women of childbearing potential: agreement to remain abstinent
(refrain from heterosexual intercourse) or use acceptable contraceptive
methods, and agreement to refrain from donating eggs.
Acceptable contraceptive methods have been listed in paragraph 4.1.1 of
protocol v2.0.
14b. For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use a condom, and agreement to refrain from donating sperm.
15. Ability to undergo and tolerate MRI scans (e.g., no claustrophobia; no
severe chorea or other condition that precludes MRI scans or renders scanning
intolerable for the patient; no MRI incompatible intrauterine devices, metallic
dental braces, or other metal implants).

1. 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.
Current suicidal ideation is demonstrated by the C-SSRS per judgement of the
Investigator. If suicidal ideation is present, a risk assessment should be done
by an appropriately qualified mental health professional to assess whether it
is safe for the patient to participate in the study. Mild passive suicidal
ideation (i.e., occasional thoughts that life is not worth living or is hard)
without history of attempts or hospitalization over the past 12 months is
generally acceptable for study participation, but final decision on
participation should be made carefully and in consultation with appropriately
qualified mental health professional.
2. Current active psychosis, confusional state, or violent behavior.
3. Any serious medical condition or clinically significant laboratory, vital
signs, or ECG abnormalities at screening that, in the Investigator's judgment,
precludes the patient's safe participation in and completion of the study.
4. Increased QTc interval (QT interval corrected through use of Fridericia's
formula [QTcF] > 470 ms), baseline resting bradycardia < 45 bpm, or baseline
resting tachycardia > 100 bpm.
5. Family history of long QT syndrome or other risk factors for torsades de
pointes.
6. History known to the Investigator or presence of an abnormal ECG that is
clinically significant in the Investigator's opinion, including complete left
bundle branch block, second- or third-degree atrioventricular heart block, or
evidence of prior myocardial infarction.
7. Clinical diagnosis of chronic migraines or history of low pressure headache
after lumbar puncture requiring hospitalization or blood patch.
8. Pregnant or breastfeeding, or intending to become pregnant during the study
or until the follow-up visit (6 months ± 2 weeks after the last dose of study
drug).
Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to initiation of study drug.
9. Presence of implanted shunt for the drainage of CSF or an implanted CNS
catheter.
10. Positive for hepatitis C virus antibody or hepatitis B surface antigen at
screening.
11. Positive for human immunodeficiency virus (HIV)-1 or HIV-2 at screening.
12. Current or previous use of an ASO (including small interfering ribonucleic
acid [RNA]).
13. Current or previous use of antipsychotics prescribed for a primary
independent psychotic disorder (i.e., schizophrenia, schizoaffective disorder,
bipolar disorder type I, severe with psychotic features), cholinesterase
inhibitors, memantine, amantadine, or riluzole within 12 weeks of enrollment.
14. Current use of antipsychotics for motor symptoms or mood stabilization
(i.e., irritability or aggressive behavior) at a dose that has not been stable
for at least 12 weeks prior to screening or is anticipated to change between
screening and treatment initiation.
15. Current use of tetrabenazine, valbenazine, or deutetrabenazine within 2
weeks prior to screening or within 6 x the elimination half-life of the
medication prior to screening (whichever is longer) or anticipated use during
the study.
16. Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a
dose that has not been stable for at least 6 weeks prior to screening or is
anticipated to change during the study.
17. Current use of antidepressant or benzodiazepine at a dose that has not been
stable for at least 12 weeks prior to screening or is anticipated to change
between screening and treatment initiation.
18. Treatment with investigational therapy within 4 weeks prior to screening or
5 drug elimination half-lives of investigational therapy, whichever is longer.
19. Antiplatelet or anticoagulant therapy within the 14 days prior to screening
or anticipated use during the study, including, but not limited to, aspirin
(unless
< 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and
apixaban.
20. History of bleeding diathesis or coagulopathy.
21. Platelet count less than the lower limit of normal.
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as the
Investigator confirms there is no evidence of current bleeding diathesis or
coagulopathy.
22. History of gene therapy or cell transplantation or any other experimental
brain surgery.
23. Concurrent or planned concurrent participation in any interventional
clinical study, including explicit pharmacological and non-pharmacological
interventions. Observational studies (e.g., ENROLL-HD prospective study) are
acceptable.
24. Illicit drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) or
alcohol abuse within 12 months prior to screening, in the Investigator's
judgment.
25. Unable or unsafe to perform lumbar puncture on the patient.
26. Previous lumbar surgery that is likely, in the opinion of the Investigator
or surgical team, to make IT catheter insertion or IT injection unduly
difficult or hazardous.
27. Poor peripheral venous access.
28. Scoliosis or spinal deformity making IT injection not feasible in the
outpatient setting.
29. Serious infection requiring oral or intravenous antibiotics within 14 days
prior to screening.
30. Antiretroviral medications.
31. Malignancy within 5 years prior to screening, except basal or squamous cell
carcinoma of the skin or carcinoma in situ of the cervix that has been
successfully treated.
32. Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous
malformation, meningiomas) as assessed by a centrally read MRI scan during the
screening period .