A phase 1/2a, open-label trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of intrathecally administered VO659 in participants with spinocerebellar ataxia types 1, 3 and Huntington*s disease

Inclusive Criteria: Participants are eligible to be included in the trial only if all of the following criteria are met: Informed Consent 1. 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. Age 2. Is >=25 and <=60 years of age inclusive, of any gender, at the time of signing the informed consent. Type of Indications and Disease Characteristics 3. Have SCA1, SCA3 or HD meeting one of the following criteria: a. SCA1 or SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of >=3 and <=18, b. HD: early manifested, 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. 4. Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG)-repeat length in the disease-causing allele by direct DNA testing (detail see Section 8.6.1), for each indication the requirements are: a. SCA1: >=41 contiguous, uninterrupted CAG repeats in ATXN1 b. SCA3: >=61 repeats in ATXN3 c. HD: >=36 CAG repeats in HTT. NOTE: Genetic testing will be performed during screening, which will serve as a reference for criterion. 5. Have good general health apart from having SCA1, SCA3, or HD at the discretion of the investigator. NOTE: In the presence a chronic illness (e.g., hypertension), a stable, well-controlled disease in the opinion of the investigator that will not impact the primary objectives of the trial is allowed. Weight 6. Have body weight of >= 50 kg and body mass index (BMI) within the range of 18-32 kg/m2 (inclusive). Reproductive status and Contraceptive/Barrier Requirements 7. Is willing to follow contraceptive requirements per local regulations regarding the methods of contraception for those participating in clinical trials. In case local regulations deviate from the contraception methods listed in Section *10.4, local regulations apply and will be described in the Informed Consent Form (CF). a. Male participants: Applicable for Europe (NOTE: details according to the Clinical Trial Facilitation Group (CTFG) Contraception Guidance Version 1.1, issued 2020; see Section 10.4): Non-sterilized males who are sexually active with a female partner of childbearing potential: Agreement to use a condom as a method of contraception during the entire period from first IMP (VO659) administration up to 90 days after the last IMP administration and not to donate sperm during this period. Additionally, contraception for the female partner of childbearing potential should be considered. b. Female participants: Applicable for Europe (NOTE: Details according to CTFG Contraception Guidance version 1.1, issued 2020; see Section 10.4): Women of childbearing potential: a negative result in a pregnancy test at screening and prior to each IMP administration AND agreement to practice a highly effective method of contraception during the entire period from informed consent up to 6 months after the last IMP administration. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for at least 12 months without an alternative medical cause. Women under the age of 55 years must have both no menses for at least 12 months and a follicle-stimulating hormone (FSH) level >40m IU/mL (while not on any therapy that may interfere with FSH levels) in order to confirm menopause. In the absence of 12 months of amenorrhea, an FSH measurement in itself is insufficient to establish menopause. Key inclusion criteria: Participants are eligible to be included in the trial only if all of the following criteria are met: Informed Consent 1. 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. Age 2. Is >=25 and <=60 years of age inclusive, of any gender, at the time of signing the informed consent. Type of Indications and Disease Characteristics 3. Have SCA1, SCA3 or HD meeting one of the following criteria: a. SCA1 or SCA3: mild to moderate disease with a Scale for Assessment and Rating of Ataxia (SARA) score of >=3 and <=18, b. HD: early manifested, 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. 4. Have genetically confirmed disease, defined by increased cytosine, adenine, and guanine (CAG)-repeat length in the disease-causing allele by direct DNA testing (detail see Section 8.6.1), for each indication the requirements are: a. SCA1: >=41 contiguous, uninterrupted CAG repeats in ATXN1 b. SCA3: >=61 repeats in ATXN3 c. HD: >=36 CAG repeats in HTT. NOTE: Genetic testing will be performed during screening, which will serve as a reference for criterion. 5. Have good general health apart from having SCA1, SCA3, or HD at the discretion of the investigator. NOTE: In the presence a chronic illness (e.g., hypertension), a stable, well-controlled disease in the opinion of the investigator that will not impact the primary objectives of the trial is allowed. Weight 6. Have body weight of >= 50 kg and body mass index (BMI) within the range of 18-32 kg/m2 (inclusive). Reproductive status and Contraceptive/Barrier Requirements 7. Is willing to follow contraceptive requirements per local regulations regarding the methods of contraception for those participating in clinical trials. In case local regulations deviate from the contraception methods listed in Section *10.4, local regulations apply and will be described in the Informed Consent Form (CF). a. Male participants: Applicable for Europe (NOTE: details according to the Clinical Trial Facilitation Group (CTFG) Contraception Guidance Version 1.1, issued 2020; see Section 10.4): Non-sterilized males who are sexually active with a female partner of childbearing potential: Agreement to use a condom as a method of contraception during the entire period from first IMP (VO659) administration up to 90 days after the last IMP administration and not to donate sperm during this period. Additionally, contraception for the female partner of childbearing potential should be considered. b. Female participants: Applicable for Europe (NOTE: Details according to CTFG Contraception Guidance version 1.1, issued 2020; see Section 10.4): Women of childbearing potential: a negative result in a pregnancy test at screening and prior to each IMP administration AND agreement to practice a highly effective method of contraception during the entire period from informed consent up to 6 months after the last IMP administration. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for at least 12 months without an alternative medical cause. Women under the age of 55 years must have both no menses for at least 12 months and a follicle-stimulating hormone (FSH) level >40m IU/mL (while not on any therapy that may interfere with FSH levels) in order to confirm menopause. In the absence of 12 months of amenorrhea, an FSH measurement in itself is insufficient to establish menopause.

Exclusion Criteria: Participants are excluded from the trial if any of the following criteria apply: Medical Conditions 1. Have any condition that would prevent participation in trial assessments. 2. Have acute infection or febrile illness at the time of each dosing, or ongoing systemic antiviral or antimicrobial therapy that will not be completed at least three days prior to dosing. 3. 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.Pathogenic mutations are defined as: >=41 contiguous, uninterrupted CAG repeats in ATXN1; >=61 repeats in ATXN3; >=36 CAG repeats in HTT; >=38 CAG repeats in AR; >=48 CAG repeats in ATN1; >=33 CAG repeats in ATXN2; >=34 CAG repeats in ATXN 7; >=20 CAG repeats in CACNA1A; >=41 CAG repeats in TBP. 4. Have clinical diagnosis of moderate or severe chronic migraines or history of the post-lumbar-puncture headache of moderate or severe intensity requiring hospitalization or blood patch. 5. Have a brain, spinal or systemic disorder that would interfere with the LP process, CSF circulation, or safety assessments. 6. 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. 7. Have a history of any malignancy or obligatory precancerous condition of any organ system, except cervical carcinoma of Stage 1B or less, or non-invasive basal cell or squamous cell skin carcinoma that has been successfully treated. 8. Have inherited or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection. 9. Have positive serology for hepatitis B surface antigen (HbsAg) or active hepatitis C infection. 10. Have any known history of hypersensitivity or allergies to the antisense oligonucleotide (AON) (VO659) or any excipient contained in the IMP. 11. Have any significant (moderate or severe) acute or chronic liver or kidney disease. 12. Have deviations of any of the following laboratory parameters at screening: • Aspartate aminotransferase (AST) >2.0 x Upper Limit of normal range (ULN) • Alanine aminotransferase (ALT) >2.0 x ULN • Total bilirubin >1.5 x ULN • Platelets <100,000/µl (i.e., <100 x 109/L) • Estimated GFR (eGFR) <45 mL/min/1.73m2 based on the modification of diet in renal disease (MDRD) formula (see Section 10.5) 13. Have uncompensated cardiovascular disorder, any past or present cardiac arrhythmia, QTcF values on screening ECG of >450 ms for males and >470 ms for females, familial history of long QT syndrome or sudden unexpected death. 14. Have a history of uncontrolled hypokalemia or hypomagnesaemia. 15. Have a history of hospitalization for any major medical or surgical procedure involving general anesthesia within 6 weeks of screening or planned during the trial. 16. Have clinical evidence of acute COVID-19 or confirmed presence of COVID-19 / SARS-CoV-2 infection at any time during the screening period, or have long-term neurological consequences of Covid-19 / SARS-CoV-2 infection that have not resolved or stabilized at the time of screening. 17. 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. For patients with (i) a suicide ideation score >= 4 on the Columbia Suicide Severity Rating Scale (C-SSRS) within the last 12 months, (ii) a score of 3 or 4 on question 2 of the Problems Behavior Assessment for Huntington*s Disease - short form or (iii) suicidal behaviours within the last 12 months (as measured by the answer *Yes* on any of the C-SSRS Suicidal Behavior Items), a risk assessment should be done by an appropriately-qualified mental health professional (e.g., a Psychiatrist or licensed Clinical Psychologist) to assess whether it is safe for the patient to participate in the study. 18. Have a history of psychosis, bipolar disorder or schizophrenia and patients deemed to be at significant risk of an acute depressive episode, confusional state or violent behaviour. 19. 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/Concomitant Therapy 20. Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter. 21. Treatment with another IMP, biological agent, or device within three months prior to screening, or five half-lives of the investigational agent, whichever is longer. 22. Riluzole use unless stable dose for at least four weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. 23. Treatment for spasticity unless stable dose for at least four weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. 24. Antidepressant or benzodiazepine use unless stable dose for at least 12 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. 25. Current or recent (within the last six months) use of antipsychotics (prescribed for psychosis) acetylcholinesterase inhibitors, memantine or amantadine. Use of antipsychotics (prescribed for treatment of motor symptoms) and/or tetrabenazine/deutetrabenazine and valproic acid is not permitted unless stable for at least 12 weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. 26. Drugs known to prolong the QT interval (see Section *10.8), unless the treatment stopped at least five times the respective drug*s elimination half-life in advance of the first dosing with VO659. 27. Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for six weeks prior to screening and with a dose regimen that is not anticipated to change during the trial. 28. Antiplatelet or anticoagulant therapy within the 14 days prior to screening or anticipated use during the trial, including but not limited to dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban; aspirin <=100 mg/day or clopidogrel are permitted. 29. Prior treatment with an antisense oligonucleotide (including siRNA). 30. History of gene therapy or cell transplantation or any experimental brain surgery. 31. Adenoviral vector-based vaccination within 45 days of the first dosing. 32. History of chemical meningitis. Prior/Concurrent Clinical Trial Experience 33. Concurrent or planned concurrent participation in any other clinical trial evaluating investigational medicinal products; for observational and non-interventional trials, the same applies, unless approved by the Sponsor*s Medical Expert or Medical Monitor.