Clinical Study of Chemogenetic Gene Therapy With AAV for Parkinson's Disease Using Stereotactic Surgery in the Subthalamic Nucleus (CGTPD)

Clinical Study of Chemogenetic Gene Therapy With Adeno-Associated Virus for Parkinson's Disease Using Stereotactic Surgery in the Subthalamic Nucleus

The investigators propose a gene therapy strategy for Parkinson's disease - a chemogenetic inhibition technique to intervene in the abnormal activity of the subthalamic nucleus in Parkinson's patients. The investigators design and construct a therapeutic injection agent called STP-001, through an efficient adeno-associated virus capsid (AAV), a neuronal promoter (hSyn), and a chemogenetic effector element (hM4Di). Then, the drug was accurately injected into the bilateral subthalamic nuclei through stereotactic surgery. After the surgery, combined with clozapine, the abnormal activity of the subthalamic nucleus was precisely intervened to improve the core motor symptoms of Parkinson's disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Parkinson's Disease (PD)
• Intervention / Treatment: Genetic: gene therapy

Detailed Description

This is a single-arm, open-label preliminary safety assessment study design. Six patients with iPD will be recruited from the Department of Neurology of the Second Affiliated Hospital of Zhejiang University School of Medicine. After signing the informed consent form, these 6 participants will be divided into 2 dose groups according to the dose escalation principle and receive the STP-001 injection solution. The virus dose escalation principle is as follows:

After 3 sentinel subjects receive 1×10¹² volts of the virus vector, the research team will assess the safety, tolerance and efficacy of the current drug dosage 3 months later. If the test subjects do not show dose-limiting toxicity and have some efficacy, the sample size will be expanded to 6 at the original dosage. If the test subjects do not show dose-limiting toxicity but have no obvious efficacy, the titer will be increased to 3×10¹² volts and three more participants will be recruited for the trial. Four weeks after the injection of STP-001, when the participants recover, clozapine dose escalation treatment will be carried out. The participants will take clozapine orally every day, with doses of 1/32, 1/16 and 1/8 tablets respectively, taken in the morning and noon, and each dose will be repeated for 3 days, totaling 9 days. If there is no disease progression during this period, the participants will continue to take the 1/8 dose of the drug twice a day as the maintenance dose and undergo monitoring for 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Jiali Pu; Phone Number: +86-13989468062; Email: Jialipu@zju.edu.cn
• Study Contact Backup: Name: Yang Ruan; Phone Number: +86-18858736151; Email: 11818236@zju.edu.cn

Study Locations

• China
  • Province
    • Zhejiang, Province, China
      • Second Affiliated Hospital, School of Medicine,Zhejiang University
      • Contact: Jiali Pu; Phone Number: +86-13989468062; Email: Jialipu@zju.edu.cn
      • Contact: Yang Ruan; Phone Number: 18858736151; Email: 11818236@zju.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age range: 40 - 70 years (inclusive), gender not restricted;
• Diagnosed with primary Parkinson's disease, with H&Y grade ranging from 4 to 5;
• Disease duration of at least 5 years;
• Response to levodopa treatment lasting for at least 12 months;
• Score of the third part of the MDS-UPDRS Part III ≥ 35;
• Improvement rate of the Madopar challenge test ≥ 30%;
• Stable clinical symptoms and drug treatment for at least 4 weeks before screening;
• Capable of understanding and voluntarily signing the informed consent form;
• Participants agree to postpone any neurological surgery, including deep brain stimulation, until the completion of 12-month follow-up;
• The efficacy of dopamine drugs has significantly decreased, or there are obvious motor complications, or severe drug side effects;
• There are no acute adverse reactions to the prescribed olanzapine dose;
• Good compliance and willing to complete all the follow-up as stipulated in this protocol.

Exclusion Criteria:

• Has a past history of brain surgery for Parkinson's disease, such as deep brain stimulation, or other abnormal brain imaging findings;
• Hamilton Depression Scale score ≥ 20;
• Hamilton Anxiety Scale score ≥ 14
• Has a history of brain injury or central nervous system infection;
• MoCA cognitive impairment score < 26 points, and MMSE dementia rating scale cognitive impairment score ≤ 20 points;
• Focal neurological deficits;
• Evidence of major medical or mental illness, such as dementia, psychosis, history of drug abuse or severe depression;
• Atypical Parkinson's disease or secondary Parkinson's disease caused by factors such as trauma, brain tumor, infection, cerebrovascular disease, other neurological diseases or drugs, chemicals or toxins;
• Received other gene or cell therapy drugs;
• Has a history of malignant tumors, but not including treated carcinoma in situ, or medical conditions that are poorly controlled and may increase the risk of surgery;
• Has a history of stroke, or obvious cardiovascular diseases, diabetes;
• Clinically obvious or laboratory-detected infections;
• Chronic immunosuppressive therapy, including chronic steroids, immunotherapy, cytotoxic therapy and chemotherapy;
• Coagulation disorders or inability to temporarily stop any anticoagulant or antiplatelet treatment before surgery;
• Severe liver disease (AST/ALT ≥ 2.5 times the upper limit of normal (ULN));
• Any factor that may prevent the subject from following the study protocol, including medical or social factors, including geographical inconvenience;
• Any other situation that the investigator deems 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: STP-001 group; This is a single-arm, open-label preliminary safety assessment study design. Six patients with iPD will be recruited from the Department of Neurology of the Second Affiliated Hospital of Zhejiang University School of Medicine. After signing the informed consent form, these 6 participants will be divided into 2 dose groups according to the dose escalation principle and receive the STP-001 injection solution. The virus dose escalation principle is as follows: After 3 sentinel subjects receive 1×10¹² volts of the virus vector, the research team will assess the safety, tolerance and efficacy of the current drug dosage 3 months later. If the test subjects do not show dose-limiting toxicity and have some efficacy, the sample size will be expanded to 6 at the original dosage. If the test subjects do not show dose-limiting toxicity but have no obvious efficacy, the titer will be increased to 3×10¹² volts and three more participants will be recruited for the trial. Four weeks after the inject

Genetic: gene therapy; Six participants are planned to be divided into two dose groups in the dose escalation principle. The dose escalation principle is as follows: After 3 sentinel subjects receive 1×10¹² volts of the virus vector, the research team will assess the safety, tolerance and efficacy of the current drug dosage 3 months later. If the test subjects do not show dose-limiting toxicity and have some efficacy, the sample size will be expanded to 6 at the original dosage. If the test subjects do not show dose-limiting toxicity but have no obvious efficacy, the titer will be increased to 3×10¹² volts and three more participants will be recruited for the trial. Four weeks after the injection of STP-001, when the participants recover, clozapine dose escalation treatment will be carried out.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence rates of adverse events and serious adverse events within 3 months after injecting STP-001 into the bilateral subthalamic nuclei.	Adverse events and serious adverse events will be evaluated through physical examinations, electrocardiogram tests and laboratory tests to assess their safety and tolerability, including routine blood tests, routine urine tests, imaging studies, etc. The main aspects include the occurrence of CRS and GvHD (≥ grade II), as well as injection-induced dyskinesia (GIDs), new-onset allogeneic tumors after injection, and death.	3 months after injecting STP-001

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence rates of adverse events and serious adverse events within 12 months after STP-001 was injected into the bilateral subthalamic nuclei.	Incidence of homologous tumor occurrence: Compare the results of head MRI scans before and after the operation, at 1, 3, 6, and 12 months; as well as the results of head CT scans before and 12 months after the operation. If there are new tumors (if any), perform histological examination to determine the pathological type. Incidence and severity of adverse events (AE) and serious adverse events (SAE): Include safety indicators such as vital signs, physical examination, laboratory tests, immunological tests, and tumor marker tests within 12 months after the operation. Evaluate injection-induced dyskinesia within 12 months after the operation using a scale.	12 months after STP-001
The differences of anti-PD drug usage before and after treatment	Compare the changes in anti-PD drug use, including daily oral levodopa or a levodopa-equivalent dose, from baseline to post-treatment in 6 participants.	12 months after STP-001 injection
The differences of the Parkinson's Disease Questionnaire before and after treatment	Compare the changes in the Parkinson's Disease Questionnaire from baseline to post-treatment in all of the 6 participants.	12 months after STP-001 injection
The differences of the Hoehn & Yahr (H&Y) stage before and after treatment	Compare the changes in the Hoehn & Yahr (H&Y) stage from baseline to post-treatment in all of the 6 participants.	12 months after STP-001 injection
The changes of the DAT PET CT before and after treatment	Compare the changes in the DAT PET CT examination, from baseline to post-treatment in 6 participants.	12 months after STP-001 injection
The differences of the MDS-Unified Parkinson's Disease Rating Scale before and after treatment	Compare the changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) from baseline to post- treatment in all of the 6 participants.Minimum value: 0；Maximum value: 260；Higher scores mean the worse outcome (greater severity of Parkinson's disease symptoms).	12 months after STP-001 injection
The differences of the Clinical Global Impression scale-improvement before and after treatment	Compare the changes in the Clinical Global Impression scale-improvement from baseline to post-treatment in all of the 6 participants.Minimum value: 1;Maximum value: 7.Higher scores mean the worse outcome (greater illness severity).	12 months after STP-001 injection
The differences of the Patient Global Impression improvement scale before and after treatment	Compare the changes in the Patient Global Impression improvement scale from baseline to post-treatment in all of the 6 participants. Minimum value: 1;Maximum value: 7.Higher scores mean worse outcome (greater illness severity).	12 months after STP-001injection
The differences of the Non-Motor Symptoms Questionnaire before and after treatment	Compare the changes in the Non-Motor Symptoms Questionnaire from baseline to post-treatment in all of the 6 participants.Minimum score of 0, Maximum score of 30.Higher scores indicate a worse outcome, reflecting a greater burden of non-motor symptoms.	12 months after STP-001 injection

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Investigators: Principal Investigator: Jiali Pu, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: April 9, 2026
• First Submitted That Met QC Criteria: April 9, 2026
• First Posted (Actual): April 16, 2026

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Parkinson's Disease; Subthalamic nucleus; clozapine; Chemical Genetic Gene Therapy
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease; Investigative Techniques; Therapeutics; Biological Therapy; Genetic Techniques; Genetic Engineering; Genetic Therapy
• Other Study ID Numbers: 2026-0355

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: As this study involves participants' personal health information, in strict compliance with the ethical approval terms and the Personal Information Protection Law, the original IPD will not be publicly shared. The data is currently stored on the secure server , and can be provided to eligible researchers under the condition of adhering to the data protection protocol. Researchers interested in conducting confirmatory or collaborative analyses can contact the corresponding author to submit a proposal.

Drug and device information, study documents

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