中文版本

Opportunity  

The treatment of neurological disorders, particularly those involving excitatory/inhibitory (E/I) imbalances such as epilepsy, remains a significant unmet medical need. Epilepsy affects millions globally, with approximately 30% of patients failing to respond to existing anti-seizure medications. Current therapies, including GABA receptor modulators, often have limited efficacy, severe side effects, or fail to address the root cause of E/I imbalance. Additionally, many low-income regions face challenges in accessing affordable and effective treatments. The development of novel therapies targeting alternative pathways, such as the G protein-coupled receptor 173 (GPR173), could provide long-lasting solutions with fewer side effects. This patent addresses the critical need for innovative treatments that restore E/I balance by targeting GPR173, a newly identified mediator of CCK-GABAergic synaptic plasticity.

Technology  

The patent discloses a recombinant adeno-associated virus (AAV) vector engineered to introduce the expression of GPR173 in neurons, specifically targeting brain regions involved in E/I imbalances. GPR173 is identified as a novel cholecystokinin (CCK) receptor that mediates the potentiation of GABAergic inhibition, distinct from known CCK1R and CCK2R receptors. The AAV vector includes a neuron-specific enhancer (e.g., CMV, CamkII, mDlx) and a BBB-penetrating PHP.eB capsid for systemic delivery. Key innovations include:  

1. Mechanism: GPR173 activation by CCK (released during high-frequency firing of CCK-GABA neurons) triggers calcium signaling, enhancing GABAergic inhibition via GABAA receptor trafficking.  
2. Delivery: The AAV vector achieves widespread brain transduction after intravenous administration, avoiding invasive brain injections.  
3. Efficacy: In vivo studies show that GPR173 upregulation suppresses seizures in chronic epilepsy models for over 8 weeks, with no adverse locomotor effects.  

Advantages  

• Target Specificity: GPR173 modulates inhibitory synapses without directly disrupting baseline GABAergic function, reducing side effects.  
• Long-lasting Effects: Single-dose administration induces sustained E/I balance restoration (potentiation lasts ≥2 months).  
• Broad Applicability: Targets multiple E/I imbalance-related disorders (epilepsy, autism, schizophrenia).  
• Non-invasive Delivery: Systemic AAV-PHP.eB crosses the BBB, enabling outpatient treatment.
• Safety: No observed cytotoxicity or behavioral abnormalities in preclinical models.  

Applications  

• Neurological Conditions:  Epilepsy (temporal lobe, focal, drug-resistant), Psychiatric disorders (schizophrenia, depression), Neurodevelopmental disorders (autism, Angelman syndrome).  
• Neurodegenerative Diseases: Alzheimer’s, Parkinson’s.  
• Trauma/Stroke: Post-injury E/I imbalance correction.  
• Gene Therapy: Scalable AAV production for clinical use.