Value Proposition:
· First Targeted Pharmacologic Therapy for SYNGAP1 (MRD5): Introduces the first mechanism-driven treatment strategy for SYNGAP1-related neurodevelopmental disorders, addressing sleep and behavioral dysfunction at the synaptic circuitry level.
· Repurposing of an FDA Approved Drug: Utilizes Perampanel (PMP), an already FDA-approved antiepileptic drug, significantly reducing regulatory barriers, development time, and safety uncertainty.
· Novel Cell-Subtype Selective Mechanism: Low-dose PMP selectively targets fast-spiking parvalbumin-positive (PV+) interneurons to restore cortical gamma oscillation homeostasis, rather than globally suppressing neuronal excitability.
· Improvement in Core Non-Seizure Symptoms: Specifically addresses sleep disturbances, disruptive behaviors, and cognitive dysfunction, which represent major unmet clinical needs in SYNGAP1 patients beyond seizure control.
· Disease Mechanism Driven Precision Therapy: Directly counteracts pathological AMPA receptor over-insertion caused by SYNGAP1 haploinsufficiency, providing a true disease-modifying approach.
· Scalable Across Developmental Epileptic Encephalopathies: While initially focused on SYNGAP1, the mechanism may extend to other disorders of cortical gamma dysregulation.
Unmet Need:
SYNGAP1-related intellectual disability (MRD5) is a rare, severe neurodevelopmental disorder marked by epilepsy, profound cognitive impairment, sleep dysregulation, and disruptive behaviors, yet there are currently no evidence-based therapies that effectively address the core sleep and behavioral symptoms. Existing antiepileptic drugs focus on seizure suppression through broad cortical inhibition, often failing to improve, and sometimes worsening, sleep and behavior, leaving families with substantial quality-of-life burdens from persistent neurobehavioral symptoms. This technology addresses this critical gap by repurposing low-dose Perampanel to selectively normalize PV+ interneuron dysfunction, offering a targeted, mechanism-based approach to improving sleep and behavioral outcomes in this population.
Technology Description:
Researchers at the Kennedy Krieger Institute have developed a novel therapeutic strategy using low-dose Perampanel (PMP) for the treatment of sleep and behavioral disorders in patients with SYNGAP1-related neurodevelopmental disease.
Low-dose Perampanel is administered at doses below conventional antiepileptic thresholds to selectively modulate AMPA receptor activity in PV+ interneurons. By restoring inhibitory control over cortical gamma oscillations, the therapy aims to normalize sleep architecture, behavioral regulation, cortical network stability, and absence seizure frequency.
Key scientific features include:
· Mechanistic Targeting of Synaptic Dysfunction: SYNGAP1 mutations cause excessive AMPA receptor insertion in fast-spiking PV+ interneurons, leading to cortical hyperexcitability and gamma oscillation disruption. Low-dose PMP reverses this abnormal synaptic physiology.
· Cell-Subtype Selectivity: Unlike conventional AED dosing that suppresses global cortical activity, this approach selectively modulates the PV+ interneuron population most affected by SYNGAP1 haploinsufficiency.
Clinical Validation and Stage of Development:
In SYNGAP1 mutant mouse models, low-dose PMP rescues excessive AMPA insertion and normalizes hyperexcitable cortical phenotypes associated with epilepsy, sleep, and behavioral dysfunction. A clinical trial is heading toward initiation at Kennedy Krieger Institute with support from Eisai IIS funding to evaluate safety and therapeutic impact on sleep, behavior, and seizure burden.
Data Availability:
· Data available upon request.
Patent Status:
18/286,185 (Status: Pending)
Select Publications:
Sullivan, Brennan J., et al. "Low-dose perampanel rescues cortical gamma dysregulation associated with parvalbumin interneuron glua2 upregulation in epileptic Syngap1+/− mice." Biological psychiatry 87.9 (2020): 829-842.
Gupta, Siddharth, et al. "Case report: Off-label use of low-dose perampanel in a 25-month-old girl with a pathogenic SYNGAP1 variant." Frontiers in Neurology 14 (2023): 1221161.
Sullivan, Brennan J., et al. "GABAergic signaling promotes early-life seizures in epileptic SYNGAP1+/-mice." bioRxiv (2020): 2020-11.
Kadam, Shilpa D. "Symphony Conductors Lose the Baton: Role of Fast-Spiking Interneurons in Orchestrating DS." Epilepsy Currents 21.3 (2021): 192-193.
Kadam, Shilpa D. "You snooze you seize: GABAergic potentiation of genetic generalized seizures during NREM." Epilepsy Currents 21.4 (2021): 290-292.
Kadam, Shilpa D., and Shane V. Hegarty. "Development of KCC2 therapeutics to treat neurological disorders." Frontiers in Molecular Neuroscience 17 (2024): 1503070.
Sullivan, Brennan J., and Shilpa D. Kadam. "Protocol for Drug Screening with Quantitative Video-Electroencephalography in a Translational Model of Refractory Neonatal Seizures." Experimental and Translational Methods to Screen Drugs Effective Against Seizures and Epilepsy. New York, NY: Springer US, 2021. 201-217.
