EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity

NCT06371794 | Enrolling By Invitation

• 1 other identifier: ID 5460
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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 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

Outcome Measures

Primary Outcomes (1)

• TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS

  Neuropsychological assessment of cognitive evaluation (Wechsler Adult Intelligence Scale)

  Through study completion, an average of 2 years

Secondary Outcomes (1)

• TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS

  Through study completion, an average of 2 years

Other Outcomes (4)

• TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS

  Through study completion, an average of 2 years

• TO CLASSIFY THE BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS

  Through study completion, an average of 2 years

• TO CLASSIFY THE BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS

  Through study completion, an average of 2 years

Study Arms (1)

To characterize in detail and classify the DS phenotype

OTHER

Patients will be stratified according to the severity of epilepsy and cognitive impairment as follows: i) Severely impaired with severe epilepsy (SISE); ii) Severely impaired with mild epilepsy (SIME); iii) Mildly impaired with severe epilepsy (MISE); iv) Mildly impaired with mild epilepsy (MIME). Mild epilepsy will be defined by: i) no history of myoclonic and/or absence seizure; ii) no history of status epilepticus; iii) seizure frequency less than weekly. Patients not fulfilling these criteria will be considered as having severe epilepsy. Cut-off for severe impairment will be defined as a z-score of more or less of -3 of adaptive behavioral or intellectual abilities scales (vineland, WISC or equivalent).

Procedure: skin punch biopsy

Interventions

skin punch biopsy PROCEDURE

skin punch biopsy (around 4 mm2) from each studied subject.

To characterize in detail and classify the DS phenotype

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Confirmed clinical diagnosis of Dravet Syndrome;
• Identification of a pathogenic variant in the SCN1A gene;
• Age between 18 and 35 years.

You may not qualify if:

• \- The presence of a significant neurological condition unrelated to Dravet Syndrome.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead
• IRCCS San Raffaele: collaborator

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00168, Italy

Location

MeSH Terms

Conditions

Epilepsies, Myoclonic

Condition Hierarchy (Ancestors)

Epilepsy, Generalized; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The ethics committee of the foundation FPG considers the study interventional since patients will undergo skin biopsy procedures ( around 4 mm)

Study Record Dates

• First Submitted: April 3, 2024
• First Posted: April 17, 2024
• Study Start: July 6, 2023
• Primary Completion: April 30, 2025
• Study Completion (Estimated): May 31, 2026
• Last Updated: April 17, 2024

Record last verified: 2024-04

Locations

IT (1)