Chemogenetic therapy in the anterior cingulate for refractory neuropathic pain

A Study of the Safety and Tolerability of GA in the Treatment of Patients With Refractory Neuropathic Pain

This study will test whether a one-time injection of GA carrying an inhibitory designer receptor into the anterior cingulate, combined with low-dose oral clozapine, can reduce severe neuropathic pain in adults whose pain has not responded to standard treatments.

Quick facts

• Phase: EARLY_PHASE1
• Study type: Interventional
• Enrollment: 6 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Beijing Tiantan Hospital (other)
• Locations: 1 site (Beijing, Beijing Municipality)
• Trial ID: NCT06596681 on ClinicalTrials.gov

What this trial studies

This early-phase 1 interventional trial uses a chemogenetic approach to deliver the hM4Di inhibitory receptor gene (via GA) directly into the anterior cingulate cortex and then activates it with oral clozapine to reduce neuronal excitability. The primary focus is safety and tolerability, with exploratory measures of pain reduction in adults with refractory neuropathic pain. Participants must have persistent neuropathic pain despite at least three months of conventional therapy and meet specified pain-intensity thresholds at baseline. The intervention is delivered intracranially at a single center (Beijing Tiantan Hospital) with planned follow-up to monitor adverse events and pain outcomes.

Who should consider this trial

Good fit: Adults aged 18–65 with a confirmed diagnosis of neuropathic pain (for example diabetic peripheral neuropathy, trigeminal neuralgia, or post‑stroke pain) who have had inadequate relief after at least three months of conventional therapies and an average VAS or NRS pain score ≥4 are candidates.

Not a fit: Patients with non‑neuropathic pain, pain below the study entry thresholds, uncontrolled medical or psychiatric conditions, or contraindications to intracranial procedures or clozapine are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, this approach could offer a targeted way to silence overactive anterior cingulate neurons and substantially reduce or eliminate treatment‑resistant neuropathic pain.

How similar studies have performed: Animal studies in multiple pain models have shown that chemogenetic inhibition of anterior cingulate neurons can eliminate pain responses, but this specific intracranial chemogenetic approach has not yet been proven in humans.

Eligibility criteria

Inclusion Criteria:

1. Patients with a definitive diagnosis of neuropathic pain, including but not limited to painful diabetic peripheral neuropathy, trigeminal neuralgia, and post-stroke pain, aged 18-65 years old (regardless of gender), with:

   1. Regularised treatment with conventional medical therapy (including, but not limited to, medication, physiotherapy, cognitive therapy, nerve blocks and other non-invasive or minimally invasive treatments) for at least 3 months with no symptomatic relief or emergence of tolerance, as assessed by the investigator
   2. Pharmacological treatment means a full course of treatment with at least two first-line medications, as assessed by the investigator
2. Mean visual analogue scale (VAS) value ≥4 cm and/or mean numerical rating scale (NRS) value ≥4 points within one week of baseline at enrolment
3. Subjects who have had a stable analgesic regimen for at least 30 days prior to the intensity of pain described in Inclusion Criterion 2 and agree not to arbitrarily change the type and dose of medication that they are currently taking until the end of the period of assessment of the effectiveness of this trial, as assessed by the investigator
4. Subjects volunteered to participate in the trial and gave fully informed consent to sign an informed consent form
5. Have stable neurological status as assessed by the researcher through motor, sensory and reflex functions
6. Subjects are considered reliable and able to comply with the trial protocol (e.g., able to understand and complete relevant scales), visit protocols, and medication administration, according to the investigator's judgement
7. Subjects of childbearing potential agree to sign an informed consent form and have no plans to have children during the study period and voluntarily use effective contraception (oral contraceptives are prohibited) and do not plan to donate sperm or eggs

Exclusion Criteria:

* 1.In patients with painful diabetic peripheral neuropathy, amputation due to diabetes mellitus or large (≥3cm) and/or gangrenous ulcers on the lower limbs 2.Currently diagnosed with progressive neurological disorders such as multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, tumours of the brain or spinal cord, and neurodegenerative disorders, as determined by the investigators 3.Have a chronic systemic disease that, as assessed by the investigator, may affect the subject's participation in the study, including but not limited to:

  1. suffering from severe cardiopulmonary disease such as unstable angina, myocardial infarction, severe arrhythmia, recurrent asthma attacks, etc;
  2. Malignant tumours of the central nervous system or other systems. 4.Current status such as coagulation disorders, bleeding tendencies, platelet dysfunction, severely reduced function due to underlying cardiac/pulmonary disease, progressive peripheral vascular disease, or poorly controlled diabetes mellitus, and subjects who may be suffering from a relevant disease state that affects surgery as assessed by the investigator 5.Currently on anticoagulants and unable to stop them 6.Localised infection or active systemic infection at the anticipated surgical access site 7.History of previous intracranial surgical treatment (except for minimally invasive paracentesis for diagnostic tests, etc.) 8.Patients with severe psychiatric symptoms (e.g., major depression, schizophrenia, etc.) or significant suicidal tendencies or assessed by the investigator to be unable to complete the clinical trial 9. Pre-existing or concomitant severe hepatic dysfunction, renal dysfunction, cardiac dysfunction (in which severe hepatic dysfunction is defined as ALT ≥ 2.0 times the upper limit of normal or AST ≥ 2.0 times the upper limit of normal; severe renal dysfunction refers to a CRE ≥ 1.5 times the upper limit of normal or an eGFR \< 40mL/min/1.73m2; and severe cardiac dysfunction refers to an NYHA score of grade 3-4) ，delirium, hypotension, epilepsy, glaucoma, myelosuppression or leukopenia, severe central nervous system depression, or coma from any cause 10. Subjects with abnormal laboratory test values:

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  1. white blood cell count \<3.5 x 109/L and neutrophil count \<1.0 x 109/L
  2. Platelet (PLT) \<75 x 109/L
  3. Coagulation: prothrombin time and activated partial thromboplastin time \>1.5 x ULN
  4. Blood adeno-associated virus (AAV) antibody titre \>1:1000 11.Patients taking drugs that cause granulocyte deficiency or have myelosuppressive effects 12.Patients with granulocyte deficiency or severe granulocytopenia due to prior clozapine use 13.Patients with contraindications and/or allergies to medications during the trial (e.g. clozapine or other components of clozapine, contrast agents, etc.) 14.Have gastrointestinal diseases (Crohn's disease, acute or chronic pancreatitis, paralytic intestinal obstruction, etc.) or major gastrointestinal surgeries that affect the absorption, metabolism and excretion of drugs, etc.

     15.Subjects had received any gene or cellular therapy 16. Known history of alcohol, drug abuse 17.Patients participating in other clinical trials or applying other investigational biologics, drugs or devices within six months prior to screening 18.Contraindications to MRI and functional MRI (e.g. claustrophobia, metallic foreign bodies in the body) 19.Clozapine-related serious adverse reactions are considered a screening failure if they occur during the screening period, at the judgement of the investigator

Where this trial is running

Beijing, Beijing Municipality

• Beijing Tiantan Hospital — Beijing, Beijing Municipality, China (RECRUITING)

Study contacts

• Study coordinator: Yahui Zhu, Doctor

Conditions: Pain, Intractable, Refractory neuropathic pain, GA, clozapine, safety