A Phase I/II Clinical Study to Evaluate the Tolerability, Safety, and Efficacy of VGN-R08b Intra-cerebroventricular injection in Parkinson's Disease Patients with GBA1 Mutations

In the open-label dose escalation part, 3 dose cohorts will be explored, with 3 subjects per cohort.

Cohort 1: 3 subjects on 4.2×10^13 vg for at least 4 weeks post infusion Cohort 2: 3 subjects on 8.4×10^13 vg for at least 4 weeks post infusion Cohort 3: 3 subjects on 1.68×10^14 vg for at least 4 weeks post infusion In the dose-escalation part, each cohort follows the principle of sentinel administration (i.e., one subject will be enrolled and dosed first in each cohort). If no significant safety risk is observed within 4 weeks after administra-tion, the remaining 2 subjects will be dosed.

Additional cohort(s) and/or a safe low and high dose will be determined by the safety review committee (SRC) to initiate Part II

Inclusion Criteria:

• Subjects must meet all the following inclusion criteria:

  1. Male or female, aged 30 to 70 years (inclusive) at the time of signing the informed consent form.
  2. Documented GBA1-mutant Parkinson's disease, confirmed by medical history: meeting the International Parkinson and Movement Disorder Society (MDS) diagnostic criteria for idiopathic Parkinson's disease, with the presence of at least one pathogenic GBA1 gene mutation (confirmed by investigator interpretation).
  3. Glucocerebrosidase (GCase) enzyme activity below the normal range, as measured from past or screening dried blood spot tests.
  4. Hoehn-Yahr stage of 3 to 4 in the "OFF" state, an MDS-UPDRS Part III (motor examination) score ≥33 points in the "OFF" state, and the ability to walk without relying on a walker or wheelchair.
  5. Montreal Cognitive Assessment (MoCA) score meeting the following criteria: >13 (for ≤6 years of education), >15 (for 7-12 years of education), or >16 (for >12 years of education) .
  6. On an optimized levodopa regimen at screening (defined as a regimen optimized with at least a combination of levodopa preparations plus a dopamine agonist or MAO-B inhibitor, with levodopa administered ≥3 times per day and at a total daily dose of ≥300 mg), yet still experiencing suboptimal symptom control or significant "wearing-off" (as evidenced by a diary documenting a daily "OFF" time of ≥2.5 hours for three consecutive days during screening).
  7. Stable Parkinson's disease symptoms and stable optimized anti-Parkinson's medication regimen for ≥4 weeks prior to screening; patients with GD-PD receiving Gaucher disease (GD) therapy must have been on stable enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) for at least 3 months prior to screening.
  8. Men and women of childbearing potential must agree to consistently and correctly use a highly effective method of contraception from the screening period until at least 1 year after dosing.
  9. Men must agree not to donate sperm, and women must agree not to donate eggs, from the screening period until at least 1 year after dosing.
  10. The patient and/or the patient's legal guardian demonstrates understanding of the trial information, purpose, and risks described in the informed consent form, and is able to authorize the use of the patient's health information by providing a signed and dated informed consent form.
  11. The patient has a reliable study partner (e.g., family member, friend, caregiver) who is willing and able to assist with study visits when needed, and to help provide information regarding the patient's health status, and cognitive and physical abilities (including providing input for rating scales).

Exclusion Criteria:

• Subject has any of the following diseases or disease history

  1. Patients with atypical or secondary parkinsonian syndromes, including but not limited to those caused by trauma, brain tumors, infections, cerebrovascular diseases, or other neurological disorders; or symptoms confirmed by the investigator to be induced by drugs, chemicals, or toxins; or those with other serious neurological conditions deemed by the investigator to significantly compromise the safety and efficacy evaluation of the investigational drug.
  2. Patients with active infections (including viral infections such as HBV, HCV, or syphilis) or a history of severe infections within 12 weeks prior to screening (e.g., pneumonia, sepsis, or central nervous system infections such as meningitis or encephalitis).
  3. Patients with severe liver disease, severe immunodeficiency, or autoimmune diseases within 6 months prior to screening, or those requiring long-term immunosuppressive therapy.
  4. Patients with poorly controlled diabetes or hypertension, judged by the investigator as unsuitable for dosing or likely to substantially impact the efficacy and safety analysis of the investigational drug.
  5. Patients with a history of stroke or transient ischemic attack (TIA), unstable angina, myocardial infarction, chronic heart failure (NYHA Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to screening.
  6. Patients with a history of epileptic seizures or unexplained coma, deemed unsuitable by the investigator for participation in the trial.
  7. Patients with a history of severe allergic reactions, or hypersensitivity to any inactive ingredient of the investigational drug or to immunosuppressants required by the trial protocol.
  8. Patients with contraindications to corticosteroids or sirolimus, including but not limited to osteoporosis with vertebral fractures within 1 year prior to screening, poorly controlled hyperlipidemia or hypercholesterolemia, renal insufficiency, or interstitial lung disease.
  9. Patients with newly diagnosed or unstable psychiatric disorders within 1 year prior to screening that may interfere with trial procedures and evaluations, including confusion, severe depression (HAMD score >35), or suicidal/self-harm tendencies.
  10. Patients with a history of malignancy within 3 years prior to screening, except for completely resected non-melanoma skin cancer, non-metastatic prostate cancer, or fully cured carcinoma in situ that has remained stable for at least 6 months.
  11. Patients with any other contraindications deemed by the investigator to potentially affect trial-related procedures, including lumbar puncture or intracerebral injection, such as spinal disorders, bleeding diathesis, clinically significant coagulation dysfunction, thrombocytopenia, or elevated intracranial pressure.