A Clinical Study of the Safety and Efficacy of Chemogenetics Therapy in the Treatment of Parkinson's Disease
Trial statusNot yet recruiting
Trial phaseEarly Phase 1
Trial typeInterventional
Biological sexAll
Age40-65
SponsorRuijin Hospital
About this trial
The investigators propose a gene therapy strategy using chemical genetic inhibition to intervene in the abnormal activity of the subthalamic nucleus in Parkinson's disease. The investigators design and construct a highly efficient therapeutic injection STP-001 (first drug), through the efficient adeno-associated virus capsid (AAV), neuronal promoter (hSyn), and chemical genetic effector element (hM4Di), and accurately inject the drug into the bilateral subthalamic nucleus, the core pathological nucleus of Parkinson's disease, through stereotactic technology. Combined with a very low dose of clozapine (the second drug), the abnormal activity of the subthalamic nucleus is precisely intervened to improve the core motor symptoms of Parkinson's disease.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Clinically diagnosed with idiopathic Parkinson's Disease [in accordance with the Diagnostic Criteria for Parkinson's Disease in China published in 2016, or in accordance with the Diagnostic Criteria for Primary PD of the International Parkinson's and Movement Disorders Society (MDS) in 2015];
Subjects aged 40-65 years old (including the boundary value), regardless of gender;
Medical history of disease ≥5 years;
Hoehn-Yahr staging scale for "off" period is 2.5-4;
Disqualifiers
Atypical or secondary Parkinson's syndrome (such as Parkinson's plus syndrome, hereditary Parkinson's syndrome, drug-induced Parkinson's syndrome);
Contraindications to surgery or previous deep brain stimulation surgery, pallidotomy, extrapyramidal surgery, other brain surgeries, or other neurosurgery that the researcher determines will affect their participation in this trial;
Previous cranial imaging suggests abnormal brain structure, cerebrovascular malformations, intracranial tumors, intracranial hemorrhage risk, brain trauma, and other abnormalities;
Mini-Mental State Examination (MMSE) score <24 points;
Trial design
Design model
Single group
Treatments tested in this trial
gene therapy
GeneticSix participants are planned to be divided into three dose groups in the dose escalation principle. The dose escalation principle is as follows: After the first sentinel subject receives 1×10¹² vg virus vectors, the research team will evaluate the safety, tolerability, and efficacy of the current drug dose after 4 weeks. If this sentinel does not experience dose-limiting toxicity, another sentinel subject will receive a 2×10¹² vg dose; if this sentinel develops dose-limiting toxicity (DLT), this dose will be defined as an intolerable dose, and the Data Review Committee will determine whether to select a lower dose for exploration or terminate dose escalation based on the existing data. If this sentinel subject doesn't experience dose-limiting toxicity, another participant will receive a 4×10¹² vg dose as a new sentinel subject. If this sentinel subject doesn't experience DLT, all of the next three subjects will receive a 4×10¹² vg dose.
clozapine
DrugClozapine ramp-up will be performed four weeks after neurosurgery, when the participants have recovered, and the participants will be treated orally with clozapine. Clozapine is 25mg per tablet, and the oral dose is 1/32, 1/16, and 1/8 tablet twice a day, in the morning and at noon, respectively, with each dose repeated for 3 days for a total of 9 days. If no DLT develops during this time, the participants will continue to take 1/8 pill orally twice a day as a maintenance dose, and they will be monitored for 12 months.
Treatment groups
6 Participants
are divided into 1 treatment groupGroup A: all of 6 patients plan to receive chemogenetic gene therapyExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
1. The incidence of adverse events and serious adverse events within 12 months after bilateral subthalamic nucleus injection of STP-001, which is the adeno-associated virus vector carrying the target gene.
Adverse events and serious adverse events will be assessed by electrocardiogram and laboratory tests for safety and tolerability assessment, including routine blood tests, routine urine tests, and blood biochemistry.
Time frame
Electrocardiogram and laboratory tests will be conducted at baseline and then prior to, during, and after the neurosurgery operation and 4, 12, 24, 36, and 48 weeks after administration of the intervention.2
2. The changes in the titer levels of the binding and capsid-neutralizing antibodies against adeno-associated virus in serum within 12 months after bilateral subthalamic nucleus injection of STP-001.
The changes in the titer levels of the binding and capsid-neutralizing antibodies against adeno-associated virus in serum will be assessed for safety and tolerability assessment.
Time frame
The titer levels of binding and capsid-neutralizing antibodies will be conducted at baseline, at the time after the neurosurgery operation, and at 12, 24, 36, and 48 weeks after administration of the intervention.Secondary outcomes
1
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.
Time frame
The anti-PD drug usage will be conducted at baseline, at the time after the neurosurgery operation, and at 12, 24, 36, and 48 weeks.2
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.
Time frame
12, 24, 36, and 48 weeks3
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.
Time frame
12, 24, 36, and 48 weeks4
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
Time frame
12, 24, 36, and 48 weeksSponsors and contacts
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Source ClinicalTrials.gov
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