Workpackages

This work package aims to collect retrospective data of the three French cohorts (KCNB1, KCNT1, KCNA2 mutated patients) using extended data acquired during clinical evaluations and patients’ follow up through the French reference network for rare epilepsies and the national bank for rare diseases.

This work package aims to collect prospective data and biosamples to enrich the structure research database developed in WP1 and feed WP5 for patient centered biomarkers identification, clusters of patients, stratification and digital twins generation.

We will develop physiologically plausible computational models able to explain the relationship between the molecular effect of a gene mutation on specific voltage gated potassium channel function and the patient-specific phenotypes observed in scalp-recorded EEG signals.

Development of targeted therapies for K-DEE patients based on cellular and animal models

• Pharmacological drugs will be repurposed for patients with KCNT1, KCNB1 and KCNA2 mutations
• Antisense oligonucleotides (ASO) will be developed for patients with KCNA2 and KCNB1 mutations
• Differential response of selected drugs and ASO will be explored on clinically driven models obtained, based on the patients phenotypes.

Several pertinent models (iPSCs, zebrafish and mouse) will be developed to test and validate therapies feeding WP6 and to bring mechanistic insights that will be exploited in WP3 for the development of computational models and in WP5 for biomarker discovery.

The first objective is to integrate all data in a single repository in order to characterize the natural history of the disease and to provide models to predict prognosis. A FAIR data set will be derived from the cohort data. The final objective is to design a digital twin prototype that integrates the mechanistic models delivered by the other work packages and a data driven multimodal model based on the Innov4-ePiK patient cohort.

Various challenges face the development and achievement of safe and effective health care in K-DEEs due to the small number of patients, the lack of robust biomarkers driven by mechanisms and by the natural history, the scarcity of patient reported outcomes (PRO) and PCOMs, as well as the use of seizure frequency decrease as the sole primary endpoint, as per current regulatory gold standard. Our objective in this work package is to develop and implement a novel clinical trial design for ultra-rare K-DEEs using a multi-component endpoint including the biomarkers validated in WP5 and the population cluster characteristics. This design will be the backbone for the pilot clinical trials testing the selected best new therapeutic strategies from repurposed compounds and ASOs obtained in WP3 and WP4.

To define and implement an efficient strategy for: scientific dissemination towards professionals and general public, engagement of patient association on project development and protecting and exploiting intellectual property rights.