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

Early Phase 1Not Yet RecruitingNCT07533591

Second Affiliated Hospital, School of Medicine, Zhejiang University6 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Interventions

gene therapyGENETIC

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.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 70 Years

Medical Language ↔ Plain English

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 Parkinson's Disease Rating Scale (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.

Outcomes

Primary Outcomes

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.

Time frame: 3 months after injecting STP-001

Secondary Outcomes

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.

Time frame: 12 months after STP-001

The differences of the MDS-Unified Parkinson's Disease Rating Scale before and after treatment

Compare the changes in the MDS-Unified Parkinson's Disease Rating Scale from baseline to post- treatment in all of the 6 participants.