ZR001 Chemogenetics Gene Therapy Study in Patients With Parkinson's Disease

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Генная терапия ZR001
  This is a prospective, open-label, single-arm, single-dose, dose-escalation, investigator-initiated trial. A sentinel-based 3+ design will evaluate three dose cohorts: 0.5E12, 1.0E12, and 2.0E12 vg/participant. One sentinel participant is enrolled per cohort; a Safety Review Committee assesses safety at 6-8 weeks post-injection before escalation. After completing escalation, remaining participants are enrolled at the selected dose for expansion. Total planned enrollment is 6-8 evaluable particip

Первичные конечные точки

• The incidence of adverse events and serious adverse events after ZR001 treatment [Срок оценки: 52 weeks]

Вторичные конечные точки (12)

• The differences of the daily levodopa equivalent dose (LED) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Clinical Global Impression - Severity (CGI-S) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Clinical Global Impression - Improvement (CGI-I) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Parkinson's Disease Questionnaire 39 (PDQ-39) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Non-Motor Symptom Scale (NMSS) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Parkinson's Disease Sleep Scale (PDSS) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Pittsburgh Sleep Quality Index (PSQI) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Montreal Cognitive Assessment (MoCA) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Mini Mental State Examination (MMSE) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Hamilton Depression Rating Scale (HAM-D) after ZR001 treatment [Срок оценки: 52 weeks]
• The differences of the Hamilton Anxiety Scale (HAM-A) after ZR001 treatment [Срок оценки: 52 weeks]

Критерии участия

Критерии включения

• 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 4.
• 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.

Критерии исключения

• 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 >1:2000.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qi — Цзинань

Идентификаторы

NCT: NCT07718659 · ZR001-101 · YXLL-KY-2026 (101)

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗