An Open-label, Single Arm, Dose-Escalation Clinical Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of ZR001, a Gene Therapy Based on Chemogenetics, for the Treatment of Parkinson's Disease
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- The incidence of adverse events and serious adverse events after ZR001 treatment
研究概览
简要总结
This study aims to evaluate the safety, tolerability, and preliminary efficacy of ZR001, a novel chemogenetic gene therapy product, in patients with moderately advanced Parkinson's disease (PD). ZR001 is administered via stereotactic injection into the bilateral substantia nigra, followed by postoperative ultra-low-dose clozapine to activate the transduced direct pathway, with the goal of improving motor symptoms of Parkinson's disease.
详细描述
This is a first-in-human (FIH), open-label, single-arm, single-dose, dose-escalation study. The trial plans to enroll 6-8 patients with moderately advanced PD across three dose cohorts: 0.5E12, 1.0E12, and 2.0E12 vg/participant. All participants will receive a single bilateral stereotactic injection into the substantia nigra under robot-assisted guidance. To mitigate immunogenicity, prophylactic corticosteroids will be administered (intravenous methylprednisolone followed by a 12-week oral prednisone taper). Four weeks after injection, oral clozapine will be titrated over 9 days to a maintenance dose of 3.125 mg (1/8 tablet) twice daily, continued through Week 52. The study includes a 60-day screening period, an inpatient stay from Day 1 to Day 7, and outpatient follow-up visits through Week 52 at Weeks 4, 8, 12, 26, 39, and 52. After completion, participants will be invited to participate in a 5-year long-term follow-up study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants who meet all of the following criteria are eligible for enrollment:
- •Age ≥40 and ≤70 years (at the time of signing the informed consent), any gender.
- •Diagnosed with Parkinson's disease according to the Diagnostic Criteria for Parkinson's Disease in China (2016 edition).
- •Modified Hoehn & Yahr stage between 2.5 and
- •History of Parkinson's disease for at least 5 years but less than 15 years.
- •Moderate to severe MDS-UPDRS Part III score in the off period, and improvement rate ≥30% after acute levodopa stress test.
- •Clinically stable symptoms and stable types and doses of anti-Parkinsonian medications within 3 months prior to enrollment.
- •Agree to provide biological samples required for the study (e.g., blood, urine).
- •Consent to hospitalization for intraparenchymal drug injection surgery.
- •Male or female participants of childbearing potential agree to use effective contraceptive methods (oral contraceptives are prohibited) from the time of signing the informed consent until at least 6 months after discontinuing clozapine.
- •Participants or their stable caregivers are able to understand and willing to comply with the study requirements and procedures, voluntarily participate, and sign the informed consent. If a caregiver is present, they must accompany the participant to study visits and assist the investigator in completing relevant scale assessments.
排除标准
- •Participants who meet any of the following criteria will be excluded from this study:
- •Have participated in or are currently participating in other clinical studies of PD drugs or other AAV gene therapy or cell therapy.
- •Presence of other severe psychiatric disorders (e.g., severe depression, schizophrenia, etc.).
- •Previous adverse reactions to clozapine, such as agranulocytosis or severe neutropenia.
- •Participants with known allergic constitution, including allergy or hypersensitivity to clozapine, prednisone acetate, other glucocorticoids, their excipients, or local anesthetics.
- •History of alcohol or drug abuse within the past 2 years.
- •Participants requiring invasive or non-invasive ventilatory support.
- •Serum AAV binding antibody titer >1:
- •Presence of clinically significant laboratory abnormalities as assessed by the investigator: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin; creatinine, hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (APTT), fasting blood glucose, platelets (PLT).
- •Presence of liver disease, heart disease, kidney disease or history thereof, which, in the investigator's assessment, may pose surgical or drug-related risks to the participant.
- •Suffering from autoimmune diseases or immunocompromised status requiring hormone or immunosuppressive therapy, which, in the investigator's assessment, may pose surgical or drug-related risks.
- •Suffering from other severe systemic diseases (e.g., cor pulmonale, moderate-to-severe asthma, etc.) that, in the investigator's assessment, may pose surgical or drug-related risks.
- •In the investigator's assessment, the participant has contraindications to anesthesia or surgery and is unsuitable for intraparenchymal administration, or other special circumstances.
- •Positive for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis C antibody, syphilis antibody, active TORCH virus infection, or active Epstein-Barr virus infection.
- •Concomitant use of any of the following medications within 90 days prior to administration, or planned immunosuppressive therapy (cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab) within 6 months after start of the trial, except for prophylactic medications specified in the protocol.
- •Pregnant or breastfeeding women, or those planning to become pregnant.
- •Other conditions that, in the investigator's opinion, make the participant unsuitable for participation in this study.
结局指标
主要结局
The incidence of adverse events and serious adverse events after ZR001 treatment
时间窗: 52 weeks
Adverse events and serious adverse events will be collected from dosing through Week 52; Including vital signs, clinical laboratory parameters, and physical examinations
次要结局
- The differences of the daily levodopa equivalent dose (LED) after ZR001 treatment(52 weeks)
- The differences of the Clinical Global Impression - Severity (CGI-S) after ZR001 treatment(52 weeks)
- The differences of the Clinical Global Impression - Improvement (CGI-I) after ZR001 treatment(52 weeks)
- The differences of the MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS) after ZR001 treatment(52 weeks)
- The differences of the Parkinson's Disease Questionnaire 39 (PDQ-39) after ZR001 treatment(52 weeks)
- The differences of the Non-Motor Symptom Scale (NMSS) after ZR001 treatment(52 weeks)
- The differences of the Parkinson's Disease Sleep Scale (PDSS) after ZR001 treatment(52 weeks)
- The differences of the Hamilton Anxiety Scale (HAM-A) after ZR001 treatment(52 weeks)
- The differences of the Pittsburgh Sleep Quality Index (PSQI) after ZR001 treatment(52 weeks)
- The differences of the Montreal Cognitive Assessment (MoCA) after ZR001 treatment(52 weeks)
- The differences of the Mini Mental State Examination (MMSE) after ZR001 treatment(52 weeks)
- The differences of the Hamilton Depression Rating Scale (HAM-D) after ZR001 treatment(52 weeks)
- The differences of the viral shedding after ZR001 treatment(52 weeks)
- The humoral and cellular immune responses to ZR001(52 weeks)
研究者
Tao Xin
Professor, Chief Physician
Qianfoshan Hospital