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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Parkinsonian Disorders; Parkinson's Disease (PD)
• Intervention / Treatment: Genetic: ZR001

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China
      • The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital)
      • Contact: Peng Zhou, Associate Chief Physician; Phone Number: 086+13954158293; Email: fzsf999@163.com
      • Principal Investigator: Tao Xin, Chief Physician & Professor
      • Sub-Investigator: Peng Zhou, Associate Chief Physician

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants who meet all of the following criteria are eligible for enrollment:

  1. Age ≥40 and ≤70 years (at the time of signing the informed consent), any gender.
  2. Diagnosed with Parkinson's disease according to the Diagnostic Criteria for Parkinson's Disease in China (2016 edition).
  3. Modified Hoehn & Yahr stage between 2.5 and 4.
  4. History of Parkinson's disease for at least 5 years but less than 15 years.
  5. Moderate to severe MDS-UPDRS Part III score in the off period, and improvement rate ≥30% after acute levodopa stress test.
  6. Clinically stable symptoms and stable types and doses of anti-Parkinsonian medications within 3 months prior to enrollment.
  7. Agree to provide biological samples required for the study (e.g., blood, urine).
  8. Consent to hospitalization for intraparenchymal drug injection surgery.
  9. 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.
  10. 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.

Exclusion Criteria:

• Participants who meet any of the following criteria will be excluded from this study:

  1. Have participated in or are currently participating in other clinical studies of PD drugs or other AAV gene therapy or cell therapy.
  2. Presence of other severe psychiatric disorders (e.g., severe depression, schizophrenia, etc.).
  3. Previous adverse reactions to clozapine, such as agranulocytosis or severe neutropenia.
  4. Participants with known allergic constitution, including allergy or hypersensitivity to clozapine, prednisone acetate, other glucocorticoids, their excipients, or local anesthetics.
  5. History of alcohol or drug abuse within the past 2 years.
  6. Participants requiring invasive or non-invasive ventilatory support.
  7. Serum AAV binding antibody titer >1:2000.
  8. 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).
  9. 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.
  10. 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.
  11. 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.
  12. In the investigator's assessment, the participant has contraindications to anesthesia or surgery and is unsuitable for intraparenchymal administration, or other special circumstances.
  13. 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.
  14. 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.
  15. Pregnant or breastfeeding women, or those planning to become pregnant.
  16. Other conditions that, in the investigator's opinion, make the participant unsuitable for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ZR001 group; The study will enroll up to 3 cohorts: low-dose, medium-dose, and high-dose ZR001 administration.

Genetic: 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 participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of adverse events and serious adverse events after ZR001 treatment	Adverse events and serious adverse events will be collected from dosing through Week 52; Including vital signs, clinical laboratory parameters, and physical examinations	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The differences of the daily levodopa equivalent dose (LED) after ZR001 treatment	Compare total daily LED (collected from dosing through Week 52) with baseline; LED is calculated using standard conversion factors for all dopaminergic medications	52 weeks
The differences of the Clinical Global Impression - Severity (CGI-S) after ZR001 treatment	Compare the change in CGI-S scores from baseline to post-treatment; CGI-S is a 7-point-scale (1 = normal to 7 = among the most extremely ill)	52 weeks
The differences of the Clinical Global Impression - Improvement (CGI-I) after ZR001 treatment	Compare the change in CGI-I scores from baseline to post-treatment; CGI-I is a 7-point-scale (1 = very much improved to 7 = very much worse)	52 weeks
The differences of the MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS) after ZR001 treatment	Change from baseline in the total UPDRS score and subscores for Parts I-IV. The UPDRS is an internationally recognized rating scale for Parkinson's disease symptoms. It comprises 4 parts assessing non-motor and motor experiences of daily living and motor complications. The total score is the sum of all 4 part scores, ranging from 0 to 183 (Part I: 0-16, Part II: 0-52, Part III: 0-56, Part IV: 0-23), with higher scores indicating greater severity of Parkinson's disease symptoms. Part I assesses non-motor experiences of daily living, including neuropsychiatric symptoms such as cognition, mood, and behavior. Part II assesses motor experiences of daily living, including activities such as writing, dressing, personal hygiene, and turning in bed. Part III assesses motor function through clinician-scored examination, including facial expression, tremor, rigidity, bradykinesia, postural instability, and gait. Part IV assesses motor complications, including dyskinesia and motor fluctuations.	52 weeks
The differences of the Parkinson's Disease Questionnaire 39 (PDQ-39) after ZR001 treatment	Compare the change from baseline to Week 52 in PDQ-39 score; The PDQ-39 is a 39-item questionnaire, with each item scored from 0 to 4, where 0 = never and 4 = always or unable to do at all. Item scores are summed, higher scores indicating worse quality of life.	52 weeks
The differences of the Non-Motor Symptom Scale (NMSS) after ZR001 treatment	Change from baseline in the NMSS total score. The NMSS is a 30-item scale covering 9 dimensions assessing non-motor symptoms in Parkinson's disease. Each item evaluates both severity and frequency of each symptom. Severity is scored from 0 to 3, where 0 = none, 1 = mild (symptom present but causes slight discomfort or distress), 2 = moderate (symptom causes some distress), and 3 = severe (symptom causes great distress). Frequency is scored from 1 to 4, where 1 = rarely (less than once a week), 2 = often (once a week), 3 = frequently (several times a week), and 4 = very frequently (daily or continuously present). For each item, the final score is calculated as severity × frequency (product). The total score is the sum of all 30 item products, ranging from 0 to 360, with higher scores indicating greater severity and higher frequency of non-motor symptoms. Units are expressed as the score on the 0-360 scale. Assessments are performed at specified post-treatment timepoints.	52 weeks
The differences of the Parkinson's Disease Sleep Scale (PDSS) after ZR001 treatment	Change from baseline in the PDSS total score. The PDSS is a 15-item scale assessing common sleep disturbances in Parkinson's disease. Each item is scored from 0 to 10, with the total score calculated as the sum of all 15 items, ranging from 0 to 150. Higher scores indicate worse sleep quality.	52 weeks
The differences of the Pittsburgh Sleep Quality Index (PSQI) after ZR001 treatment	Change from baseline to Week 52 in PSQI global score; The PSQI is a standardized instrument developed by the Sleep Research Center at the University of Pittsburgh Medical Center for assessing sleep quality. It comprises 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored, and the total score is ranging from 0 to 21. Higher scores indicate worse sleep quality, with a total score >5 generally considered indicative of poor sleep quality.	52 weeks
The differences of the Montreal Cognitive Assessment (MoCA) after ZR001 treatment	Change from baseline to Week 52 in MoCA total score; The MoCA is a neuropsychological assessment tool developed by Nasreddine and colleagues in 2004 at McGill University, Canada. It covers 8 cognitive domains, including attention and concentration, executive functions, memory, language, and visuospatial skills, and comprises 11 testing tasks such as the Trail Making Test (alternating), cube copying, and delayed recall of memory. The total score is ranging from 0 to 30. A score of ≥26 is generally considered as normal, with lower scores indicating cognitive impairment.	52 weeks
The differences of the Mini Mental State Examination (MMSE) after ZR001 treatment	Change from baseline in the MMSE total score. The MMSE is a screening tool for cognitive and intellectual function impairment in the elderly, developed by Folstein and colleagues in 1975 in the United States. The scale comprises 5 cognitive domains: orientation, registration(memory), attention and calculation, recall, and language. Each item is scored 1 point for a correct answer, and 0 points for an incorrect answer or unknown. The total score ranges from 0 to 30, with higher scores indicating better cognitive function. The cut-off for dementia is adjusted by educational level: <17 for illiterate individuals, <20 for primary school education, and <24 for middle school education or above are considered indicative of dementia. Severity reference: 27-30 = normal, 21-26 = mild, 10-20 = moderate, and 0-9 = sever	52 weeks
The differences of the Hamilton Depression Rating Scale (HAM-D) after ZR001 treatment	Change from baseline in the HAM-D total score. The HAM-D is a clinician-rated scale developed by Hamilton in 1960 for assessing the severity of depressive symptoms and evaluating treatment response. Assessments are performed through interview and observation. The total score is calculated as the sum of all item scores, ranging from 0 to 52, with higher scores indicating greater severity of depression. Clinical interpretation: total score < 8 = normal; 8-20 = possible depression; 20-35 = definite depression; > 35 = severe depression. A score of ≥ 20 is generally considered to indicate moderate to severe depressive symptoms.	52 weeks
The differences of the Hamilton Anxiety Scale (HAM-A) after ZR001 treatment	Change from baseline in the HAM-A total score. The HAM-A can be used to evaluate the severity of anxiety symptoms in patients with anxiety and depressive disorders, as well as to assess treatment response to various pharmacological and psychological interventions. All items are rated on a 5-point scale from 0 to 4, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. The total score is calculated as the sum of all item scores, ranging from 0 to 56, with higher scores indicating greater severity of anxiety. Clinical interpretation: total score < 7 = no anxiety; 7-13 = possible anxiety; 14-20 = definite anxiety; 21-28 = definite marked anxiety; ≥ 29 = severe anxiety. Additionally, scores of ≥ 17, ≥ 25, and ≥ 30 are commonly used as thresholds for mild, moderate, and severe anxiety respectively.	52 weeks
The differences of the viral shedding after ZR001 treatment	Detection of vector DNA by qPCR in blood, saliva, urine, and feces at baseline and at Day 7, Weeks 4, 8, 12, 26, 39, and 52 post-dose	52 weeks
The humoral and cellular immune responses to ZR001	Change from baseline to Week 52 in humoral and cellular immune responses to ZR001	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The differences of the brain MRI performance after ZR001 treatment	Change from baseline to Week 52 in MRI parameters	52 weeks
The differences of the electromyography (EMG) tremor analysis after ZR001 treatment	Change from baseline to Week 52 in EMG tremor analysis	52 weeks
The differences of the orthostatic blood pressure regulation after ZR001 treatment	Change from baseline in orthostatic blood pressure response (systolic and diastolic) measured during supine to standing test	52 weeks
The differences of the polysomnography (PSG) parameters after ZR001 treatment	Change from baseline in polysomnography (PSG) parameters	52 weeks

Collaborators and Investigators

• Sponsor: Qianfoshan Hospital
• Collaborators: Shenzhen Loongen Biotechnology Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: July 1, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Parkinson's Disease; Clozapine; Movement Disorders; Central Nervous System Diseases; Neurodegenerative Diseases; AAV; PD; DREADD; D1-MSN; Chemogenetics
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Nervous System Diseases; Basal Ganglia Diseases; Movement Disorders; Parkinson Disease; Neurodegenerative Diseases; Central Nervous System Diseases; Parkinsonian Disorders
• Other Study ID Numbers: ZR001-101; YXLL-KY-2026 (101) (Other Identifier: EC of The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No