Dravet SyndromeEXEDRANCT06371794
EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity
A study testing skin punch biopsy in people with Dravet Syndrome, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Dravet Syndrome
- What is being tested?
- skin punch biopsy
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteItaly
- Study dates
- 6 Jul 2023to 31 May 2026
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Confirmed clinical diagnosis of Dravet Syndrome;
- Identification of a pathogenic variant in the SCN1A gene;
- Age between 18 and 35 years.
Who cannot join
- The presence of a significant neurological condition unrelated to Dravet Syndrome.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Exploring Novel Molecular Determinants of Dravet Syndrome Phenotype Heterogeneity
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.
Read the 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 cognitive/behavioral 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.
- Conditions
- Dravet Syndrome
- Being tested
- skin punch biopsy
- Medical subject headings
- Epilepsies, Myoclonic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
skin punch biopsyProcedure or surgery
skin punch biopsy (around 4 mm2) from each studied subject.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Procedure: skin punch biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS
Neuropsychological assessment of cognitive evaluation (Wechsler Adult Intelligence Scale)
Measured: Through study completion, an average of 2 years
Secondary outcomes (1)
TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS
Neuropsychological assessment of adaptive behavior (Vineland-II scale).
Measured: Through study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Apr 2024
- Study start6 Jul 2023
- Primary completion30 Apr 2025 (estimated)
- Study completion31 May 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Dravet SyndromeStudies of the same condition, open and under way.
- More trials run by Fondazione Policlinico Universitario Agostino Gemelli IRCCSThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The ethics committee of the foundation FPG considers the study interventional since patients will undergo skin biopsy procedures ( around 4 mm)
- Masking
- None (open label)
- Enrolment
- 16 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- IRCCS San Raffaele
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06371794
- Sponsor's protocol ID
- ID 5460
- Acronym
- EXEDRA
- Status last verified
- Apr 2024
- First submitted
- 3 Apr 2024
- Last updated
- 17 Apr 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploring Novel Molecular Determinants of Dravet Syndrome Phenotype Heterogeneity
- ClinicalTrials.gov ID
- NCT06371794
- Acronym / sponsor ID
- EXEDRA / ID 5460
- Conditions
- Dravet Syndrome
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 16 participants (estimated)
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
- Collaborators
- IRCCS San Raffaele
- Study start
- 6 Jul 2023 (actual)
- Primary completion
- 30 Apr 2025 (estimated)
- Study completion
- 31 May 2026 (estimated)
- First posted
- 17 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 cognitive/behavioral 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 design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The ethics committee of the foundation FPG considers the study interventional since patients will undergo skin biopsy procedures ( around 4 mm)
| Arm | Type | Receives |
|---|---|---|
| To characterize in detail and classify the DS phenotype | Other | Procedure: skin punch biopsyPatients 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). |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Confirmed clinical diagnosis of Dravet Syndrome;
- Identification of a pathogenic variant in the SCN1A gene;
- Age between 18 and 35 years.
Key exclusion criteria (1 listed)
- The presence of a significant neurological condition unrelated to Dravet Syndrome.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| skin punch biopsyskin punch biopsy (around 4 mm2) from each studied subject. | Procedure or surgery | To characterize in detail and classify the DS phenotype |
Primary outcome
TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS
Time frame: Through study completion, an average of 2 years
Neuropsychological assessment of cognitive evaluation (Wechsler Adult Intelligence Scale)
1 secondary outcome
TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS
Time frame: Through study completion, an average of 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Apr 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing skin punch biopsy in people with Dravet Syndrome, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
TO CLASSIFY THE COGNITIVE/BEHAVIORAL PHENOTYPE SEVERITY OF DS PATIENTS (time frame: Through study completion, an average of 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Apr 2024.