nctId: NCT06371794 id: ID 5460 briefTitle: EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity acronym: EXEDRA overallStatus: ENROLLING_BY_INVITATION date: 2023-07-06 date: 2025-04-30 date: 2026-05-31 date: 2024-04-17 date: 2024-04-17 name: Fondazione Policlinico Universitario Agostino Gemelli IRCCS class: OTHER name: IRCCS San Raffaele briefSummary: Dravet syndrome is characterized as a developmental encephalopathy resulting from mutations of SCN1A, the gene encoding the alpha subunit of the voltage-gated sodium channel Nav1.1. The syndrome typically presents with drug-resistant epilepsy and varying degrees of cognitive disorders. Current treatment efficacy may be hindered by insufficient knowledge of undiscovered molecular determinants of the disease and its heterogeneous nature. Utilizing induced pluripotent stem cells (iPSCs) derived from skin biopsies, accessibility to patients' brain neurons has enabled successful modeling of various genetic neurological diseases. Neurons and brain organoids will be obtained from Dravet syndrome patients exhibiting diverse phenotypic severities, encompassing behavioral and developmental delays, to discern the molecular determinants of phenotypic diversity. Specifically, emphasis will be placed on investigating cellular and molecular mechanisms linking altered neuronal excitability with synaptic dysfunction.The study will focus on exploring the expression of newly identified modifiers potentially associated with neuronal excitability and synaptic function in iPSC-derived human neurons. This aims to establish correlations between the severity of epileptic and cognitive phenotypes and the altered expression of these proteins, whose functions are not fully understood.In the mid to long term, efforts will be directed towards overcoming the limitations of conventional therapeutic approaches for Dravet syndrome. This will involve attempting to reverse the observed morphological and functional alterations in Dravet syndrome neurons using viral vectors to promote overexpression/downregulation of identified modifiers correlated with disease severity. The anticipated outcomes of this project are expected to unveil novel molecular mechanisms underlying the pathophysiology of this severe neurogenetic disease, characterized by varying degrees of cognitive impairment. Moreover, these findings may pave the way for the discovery of innovative therapeutic strategies. conditions: Dravet Syndrome studyType: INTERVENTIONAL phases: NA allocation: NA interventionModel: SINGLE_GROUP interventionModelDescription: The ethics committee of the foundation FPG considers the study interventional since patients will undergo skin biopsy procedures ( around 4 mm) primaryPurpose: BASIC_SCIENCE masking: NONE count: 16 type: ESTIMATED name: skin punch biopsy measure: TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS measure: TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS measure: TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS measure: TO CLASSIFY THE BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS measure: TO CLASSIFY THE BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS measure: TO CLASSIFY THE EPILEPTIC PHENOTYPE SEVERITY OF DS PATIENTS sex: ALL minimumAge: 18 Years maximumAge: 35 Years stdAges: ADULT facility: Fondazione Policlinico Universitario A. Gemelli IRCCS city: Roma zip: 00168 country: Italy lat: 41.89193 lon: 12.51133 hasResults: False