Ignite Creation Date:
2024-05-06 @ 8:25 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06371794
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2024-04-17
First Post:
2024-04-03
Brief Title:
EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity
Sponsor:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Organization:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Study Overview
Official Title:
Exploring Novel Molecular Determinants of Dravet Syndrome Phenotype Heterogeneity
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EXEDRA
Brief Summary:
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 Nav11 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 dysfunctionThe 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 understoodIn 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 overexpressiondownregulation 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
Detailed Description:
Dravet Syndrome DS is characterized as both an epileptic encephalopathy where seizures contribute to phenotype severity and a developmental encephalopathy where genetic background directly impacts developmental delay independently from seizure activity The syndrome exhibits significant heterogeneity in phenotype severity with polymorphic seizures typically occurring before age 12 months and progressing with varying severity Additionally cognitive and behavioral impairments become apparent during the second year of life or later worsening with age and seizure frequency Factors limiting the efficacy of current treatments likely include insufficient knowledge of unknown molecular determinants of the disease and its heterogeneity To address this novel molecular modifiers linked to excitability and synaptic function are hypothesized to unveil the pathophysiology of DS phenotype heterogeneity The study aims to investigate hiPSCs-derived neurons from DS patients compared with age-matched healthy subjects Specifically skin biopsies will be obtained from DS patients and healthy controls to generate neurons and brain organoids These models will be utilized to understand how changes in excitability and synaptic function affect phenotype severity in DS and to identify new molecular determinants associated with altered neuronal excitability and synaptic dysfunction Aims of the study include classifying the epileptic and cognitivebehavioral phenotype severity of DS patients characterizing neurons and brain organoids obtained from DS patients and identifying potential phenotype modifiers Additionally the study aims to provide proof of concept for the development of novel modifier-related pharmacogenetic strategies to alleviate or rescue DS phenotype Recruitment of DS patients and healthy controls will be conducted and various assessments will be performed to classify phenotype severity Functional morphological and molecular alterations in human neurons derived from DS patients will be investigated using a range of experimental techniques Ultimately the study seeks to deepen understanding of DS pathophysiology identify potential therapeutic targets and pave the way for personalized medicine approaches tailored to individual patients molecular profiles
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None