A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD

Main Inclusion Criteria: Provide written informed consent (signed and dated). Patients should be assessed for their ability to give informed consent using the Evaluation to Sign Consent tool. Is ≥25 and ≤60 years of age inclusive, of any gender, at the time of signing the informed consent. Have SCA1, SCA3 or HD meeting one of the following criteria: SCA1 and SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of ≥3 and ≤18 HD: early manifest, Stage I disease with a Total Functional Capacity (TFC) Score of ≥11 and ≤13 and a Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4. Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG) repeat length in the disease-causing allele by direct DNA testing. For each indication the requirements are: SCA1: ≥41 contiguous, uninterrupted CAG repeats in the ATXN1 gene SCA3: ≥61 repeats in the ATXN3 gene HD: ≥36 CAG repeats in the HTT gene. Please note there will be additional inclusion criteria Main Exclusion Criteria: Have any condition that would prevent participation in trial assessments. Have one or more pathogenic mutation(s) in another polyQ disease gene, i.e., ATXN2, CACNA1A, ATXN7, TBP, AR, and ATN1, plus either ATXN3 and HTT (for patients with SCA1), ATXN1 and HTT (for participants with SCA3), or ATXN1 and ATXN3 (for participants with HD), in addition to the disease-causing mutation in the ATXN1 (patients with SCA1), ATXN3 (patients with SCA3) or HTT (patients with HD) gene. Have clinical diagnosis of moderate or severe chronic migraines or history of the post-lumbar-puncture headache of moderate or severe intensity requiring hospitalisation or blood patch. Have a brain, spinal or systemic disorder that would interfere with the LP process, CSF circulation, or safety assessments. Have history of bleeding diathesis or coagulopathy, platelet count less than the lower limit of normal unless stable and assessed by the investigator and the Medical Monitor to be not clinically significant. Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, QTcF values on screening ECG of >470 ms, familial history of long QT syndrome or sudden unexpected death. Have a history of attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to screening. Have medical, psychiatric, or other conditions that, in the judgement of the investigator, may compromise the patient's ability to understand the patient information sheet, to give informed consent, to comply with all trial requirements, or to complete the trial. Prior treatment with an antisense oligonucleotide (including siRNA). Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial. Unable to undergo and tolerate MRI scans. Please note there will be additional exclusion criteria