Project ID NS-MH2023_59

ThemeNS-MH

Co Supervisor 1A IoPPN/Basic and Clinical NeuroscienceWebsite

Co Supervisor 1B IoPPN/Basic & Clinical NeuroscienceWebsite

Precision Medicine in Genetic Epilepsies: Developing a Human Induced Pluripotent Cell Biobank and Testing Platform to Diagnose and Predict Treatment Effects in Complex Epilepsies

Human induced pluripotent stem cells (hiPSCs) derived from patients with neurological disease are an invaluable source to study the development of central nervous system disorders such as epilepsy. In a novel approach, we will investigate if hiPSCs from epilepsy patients carrying genetic variants of uncertain significance may help elucidate pathogenicity and response to antiseizure medication, paving a way for a rapid, simple but revolutionary tool to deliver precision medicine diagnosis and treatment.

Aims:
– To develop an hiPSC bank from patients with known pathogenic germline mutations causing epilepsy and characterise their histology, neurophysiology and response to antiseizure drugs. Subsequently, to compare skin fibroblast-derived hiPSCs with hiPSC derived from nasal mucosal swabs.
– To establish if hiPSCs grown on multielectrode arrays could become a first stage screening tool for novel mutations of uncertain significance.
– To engineer hiPSC with mammalian Target of Rapamycin (mTOR) mutations from patients with focal cortical dysplasia (FCD) as novel platform to test mTOR inhibitor treatment and predict surgical outcome.

HiPSC derivation, histological and neurophysiological in vitro techniques, deep phenotyping and epidemiology of genetic epilepsy patients, database and Biobank development.

Objectives:
Year 1: Acquisition of Technical (hiPSC culture, histology and in vitro neurophysiology) and Clinical Skills (Deep phenotyping of Epilepsy patients, Genetic epilepsy clinics)
Year 2: HiPSC Bank Development (; detailed histological, neurophysiological and pharmacological characterisation)
Year 3: Translating Results from Bench to Bedside (Comparing experimental and clinical outcomes, development of diagnostic tool for predicting network effect of genetic mutations and treatment efficacy).

Representative Publications

Wykes RC*, Heeroma JH*, Mantoan L*, Zheng K, Macdonald DC, Deisseroth K, Hashemi KS, Walker MC, Schorge S, Kullmann DM. * joint first authors. Optogenetic and Potassium Channel Gene Therapy in a Rodent Model of Focal Neocortical Epilepsy. Science Translational Medicine 2012;4(161):161fs40.

King A, Szekely B, Calapkulu E, Ali H, Rios F, Jones S, Troakes C.

The Increased Densities, But Different Distributions, of Both C3 and S100A10 Immunopositive Astrocyte-Like Cells in Alzheimer’s Disease Brains Suggest Possible Roles for Both A1 and A2 Astrocytes in the Disease Pathogenesis.

Brain Sci. 2020 Jul 31;10(8):503. doi: 10.3390/brainsci10080503.