Periodic Reporting for period 1 - EpiSen (Senolytics repurposing in childhood refractory epilepsies)
Reporting period: 2023-07-01 to 2024-12-31
Focal Cortical Dysplasia (FCD) is a rare neurological disorder representing up to 39% of pediatric epilepsy surgery cases. These conditions manifest as drug-resistant seizures with developmental delays in early childhood. Over 80% of FCD patients do not respond to conventional antiepileptic drugs, making invasive neurosurgical resection the primary treatment option.
Recent research has advanced understanding of FCD pathophysiology, demonstrating that most cases result from brain somatic mutations in mTOR pathway genes (MTOR, PIK3CA, AKT3, DEPDC5). These mutations create a mosaic pattern where abnormal cytomegalic cells display mTOR hyperactivity and generate epileptogenic activity. Current approaches targeting the mTOR pathway systemically have shown limited efficacy, as demonstrated by clinical trials with rapamycin/everolimus that failed to significantly reduce seizures.
Building on findings from the EpiTOR ERC Consolidator Grant, our research identified cellular senescence signatures specifically present in abnormal FCD cells. FCDII tissues consistently display senescence hallmarks, including p53/p16 expression and senescence-associated β-galactosidase activity, exclusively in pathogenic mutated cells responsible for seizure generation, unlike normal brain tissue or other epilepsy types.
This discovery enables a precision medicine approach using senolytic drugs—FDA-approved agents that selectively eliminate senescent cells through targeted apoptosis. Our preliminary data shows that oral administration of dasatinib plus quercetin (DQ) effectively clears abnormal senescent cells and reduces seizure frequency in preclinical mouse models, offering a "hit-and-run" therapeutic strategy that may provide sustained seizure control without chronic medication.
Overall Objectives: EpiSen aims to translate this scientific discovery into clinically viable precision therapy for childhood refractory epilepsies through three objectives: (1) Preclinical validation of senolytic therapy in two distinct FCD mouse models, demonstrating senescent cell clearance and sustained seizure reduction; (2) Intellectual property protection, Orphan Drug Designation pursuit, and strategic pharmaceutical partnerships; (3) Design Phase 2 clinical trial testing DQ combination in children with drug-resistant FCD-related epilepsy.
Expected Impact: EpiSen could significantly advance childhood epilepsy treatment. Unlike symptomatic treatments, this approach targets underlying pathophysiology through selective elimination of epileptogenic cells, potentially offering sustained seizure control, precision targeting that preserves normal brain tissue, broad applicability regardless of specific mutations, reduced need for surgical intervention, and improved quality of life. This therapeutic strategy may extend to other "mTORopathies" including tuberous sclerosis complex, contributing to precision medicine development in rare neurological disorders. The approach addresses an important unmet medical need and could establish new treatment paradigms for rapid translation of mechanistic discoveries into clinical therapies.
Recent research has advanced understanding of FCD pathophysiology, demonstrating that most cases result from brain somatic mutations in mTOR pathway genes (MTOR, PIK3CA, AKT3, DEPDC5). These mutations create a mosaic pattern where abnormal cytomegalic cells display mTOR hyperactivity and generate epileptogenic activity. Current approaches targeting the mTOR pathway systemically have shown limited efficacy, as demonstrated by clinical trials with rapamycin/everolimus that failed to significantly reduce seizures.
Building on findings from the EpiTOR ERC Consolidator Grant, our research identified cellular senescence signatures specifically present in abnormal FCD cells. FCDII tissues consistently display senescence hallmarks, including p53/p16 expression and senescence-associated β-galactosidase activity, exclusively in pathogenic mutated cells responsible for seizure generation, unlike normal brain tissue or other epilepsy types.
This discovery enables a precision medicine approach using senolytic drugs—FDA-approved agents that selectively eliminate senescent cells through targeted apoptosis. Our preliminary data shows that oral administration of dasatinib plus quercetin (DQ) effectively clears abnormal senescent cells and reduces seizure frequency in preclinical mouse models, offering a "hit-and-run" therapeutic strategy that may provide sustained seizure control without chronic medication.
Overall Objectives: EpiSen aims to translate this scientific discovery into clinically viable precision therapy for childhood refractory epilepsies through three objectives: (1) Preclinical validation of senolytic therapy in two distinct FCD mouse models, demonstrating senescent cell clearance and sustained seizure reduction; (2) Intellectual property protection, Orphan Drug Designation pursuit, and strategic pharmaceutical partnerships; (3) Design Phase 2 clinical trial testing DQ combination in children with drug-resistant FCD-related epilepsy.
Expected Impact: EpiSen could significantly advance childhood epilepsy treatment. Unlike symptomatic treatments, this approach targets underlying pathophysiology through selective elimination of epileptogenic cells, potentially offering sustained seizure control, precision targeting that preserves normal brain tissue, broad applicability regardless of specific mutations, reduced need for surgical intervention, and improved quality of life. This therapeutic strategy may extend to other "mTORopathies" including tuberous sclerosis complex, contributing to precision medicine development in rare neurological disorders. The approach addresses an important unmet medical need and could establish new treatment paradigms for rapid translation of mechanistic discoveries into clinical therapies.
Preclinical Validation
1/ We have extended the validation of senescent hallmarks in additional FCD2 tissues from surgical resections, as well as other mTORopathies (TSC)
2/ We have generated a new group of mice by in utero electroporation to test new senolytics and replicate previous findings. We will demonstrate clearance of senescent cells through quantification of senescence-associated β-galactosidase activity, following 9-day oral senolytic administration. Video-EEG monitoring will be used to monitor seizure frequency reduction, with sustained therapeutic benefits extending 6 months post-treatment, validating the "hit-and-run" concept.
IP Protection and Industrial Partnerships
1/ We completed comprehensive patentability study for repurposed senolytics in epilepsy, which concluded that patent protection was not eligible due to a confidentiality breach that compromised novelty requirements. Patent application filing was therefore unsuccessful. For repositioning of existing therapeutic agents, the Orphan Drug Designation pathway represents the most appropriate protection strategy.
2/ Submission to Orphan Drug Designation application has not been initiated yet. We have gathered enough data to support this process and plan to submit the application in the upcoming year, in order to raise the attractivity of the project for pharma companies.
3/ We are in the process of establishing formal collaboration agreements with key industrial partners (confidentiality and research agreements ongoing).
4/ We developed comprehensive Data Management Plan ensuring FAIR data principles compliance.
Clinical Trial Design and Authorization has not been initiatd in the timeframe of the project
Project Management and Dissemination
1/ We implemented project management structure with quarterly steering committee meetings ensuring coordinated progress across all work packages.
2/ We achieved significant scientific dissemination through one key publication in Nature Neuroscience (Ribierre et al. 2024), and 3 international conference presentations.
1/ We have extended the validation of senescent hallmarks in additional FCD2 tissues from surgical resections, as well as other mTORopathies (TSC)
2/ We have generated a new group of mice by in utero electroporation to test new senolytics and replicate previous findings. We will demonstrate clearance of senescent cells through quantification of senescence-associated β-galactosidase activity, following 9-day oral senolytic administration. Video-EEG monitoring will be used to monitor seizure frequency reduction, with sustained therapeutic benefits extending 6 months post-treatment, validating the "hit-and-run" concept.
IP Protection and Industrial Partnerships
1/ We completed comprehensive patentability study for repurposed senolytics in epilepsy, which concluded that patent protection was not eligible due to a confidentiality breach that compromised novelty requirements. Patent application filing was therefore unsuccessful. For repositioning of existing therapeutic agents, the Orphan Drug Designation pathway represents the most appropriate protection strategy.
2/ Submission to Orphan Drug Designation application has not been initiated yet. We have gathered enough data to support this process and plan to submit the application in the upcoming year, in order to raise the attractivity of the project for pharma companies.
3/ We are in the process of establishing formal collaboration agreements with key industrial partners (confidentiality and research agreements ongoing).
4/ We developed comprehensive Data Management Plan ensuring FAIR data principles compliance.
Clinical Trial Design and Authorization has not been initiatd in the timeframe of the project
Project Management and Dissemination
1/ We implemented project management structure with quarterly steering committee meetings ensuring coordinated progress across all work packages.
2/ We achieved significant scientific dissemination through one key publication in Nature Neuroscience (Ribierre et al. 2024), and 3 international conference presentations.
Revolutionary Precision Medicine Approach: EpiSen establishes the first precision therapy specifically targeting the cellular pathophysiology underlying FCD-related epilepsy. Unlike conventional antiepileptic drugs that provide symptomatic management, our senolytic approach directly eliminates the pathogenic senescent cells responsible for epileptogenesis. This represents a paradigm shift from chronic symptomatic treatment to potentially curative intervention through selective cellular ablation.
Universal Therapeutic Strategy: The senescence-targeting approach transcends specific genetic mutations, offering universal applicability across all FCDII subtypes regardless of the underlying mTOR pathway mutation. This broad therapeutic scope addresses the genetic heterogeneity challenge that has hindered previous precision medicine efforts in epilepsy, potentially benefiting the entire FCDII patient population.
Breakthrough "Hit-and-Run" Therapy: Our results demonstrate sustained therapeutic benefits extending 6 months post-treatment, validating the innovative concept of short-term intervention providing long-lasting seizure control.
Universal Therapeutic Strategy: The senescence-targeting approach transcends specific genetic mutations, offering universal applicability across all FCDII subtypes regardless of the underlying mTOR pathway mutation. This broad therapeutic scope addresses the genetic heterogeneity challenge that has hindered previous precision medicine efforts in epilepsy, potentially benefiting the entire FCDII patient population.
Breakthrough "Hit-and-Run" Therapy: Our results demonstrate sustained therapeutic benefits extending 6 months post-treatment, validating the innovative concept of short-term intervention providing long-lasting seizure control.