Periodic Reporting for period 1 - NaV1.5-CARED (NaV1.5 regulation fine-tuning as a therapy for cardiac Conduction and Arrhythmic diseases at Risk of suddEn Death)
Reporting period: 2023-10-01 to 2024-09-30
The voltage-gated sodium channel NaV1.5 is essential for cardiac function. Its dysfunction can cause ventricular fibrillation and sudden cardiac death, making it a critical target for therapies aimed at preventing life-threatening arrhythmias. Current treatments, such as implantable cardioverter defibrillators and pacemakers, are invasive and costly. The NaV1.5-CARED consortium seeks to identify regulatory elements and proteins influencing NaV1.5 expression and function, aiming to develop innovative therapies.
The project has three main objectives:
Risk Prediction: Develop polygenic risk scores (PRS) to predict individual risk of fatal arrhythmias.
Mechanistic Insights: Uncover molecular mechanisms linking regulatory regions and cardiac disease to identify new therapeutic targets.
Therapeutic Development: Create therapies to restore NaV1.5 function.
Following database harmonization, whole-genome studies will identify variants linked to arrhythmias and conduction defects, enabling PRS development for risk stratification. Identified targets will be tested in high-throughput models using cardiomyocytes derived from induced pluripotent stem cells.
Impact on Cardiology Practice
The project will reshape clinical management of Brugada syndrome (BrS) patients, where currently only SCN5A mutations (found in 20% of cases) are considered for genetic risk. Introducing PRS will improve risk stratification and individualized care, reducing unnecessary device implantation. The first therapy restoring NaV1.5 function will further transform treatment options, moving beyond current device-based interventions.
Personalized care in CardioVascular Disease (CVD)
BrS-PRS has already shown potential for identifying individuals with conduction abnormalities in the general population. Interestingly, genetic variants linked to BrS appear protective against atrial fibrillation, a common arrhythmia.
Beyond the Project's Scope
NaV1.5-CARED will develop hiPSC-derived cardiomyocyte models for high-throughput analysis of NaV1.5 expression, localization, and sodium current density. These models could also be used to test drug safety, aligning with CiPA guidelines for assessing proarrhythmic risks.
The project has three main objectives:
Risk Prediction: Develop polygenic risk scores (PRS) to predict individual risk of fatal arrhythmias.
Mechanistic Insights: Uncover molecular mechanisms linking regulatory regions and cardiac disease to identify new therapeutic targets.
Therapeutic Development: Create therapies to restore NaV1.5 function.
Following database harmonization, whole-genome studies will identify variants linked to arrhythmias and conduction defects, enabling PRS development for risk stratification. Identified targets will be tested in high-throughput models using cardiomyocytes derived from induced pluripotent stem cells.
Impact on Cardiology Practice
The project will reshape clinical management of Brugada syndrome (BrS) patients, where currently only SCN5A mutations (found in 20% of cases) are considered for genetic risk. Introducing PRS will improve risk stratification and individualized care, reducing unnecessary device implantation. The first therapy restoring NaV1.5 function will further transform treatment options, moving beyond current device-based interventions.
Personalized care in CardioVascular Disease (CVD)
BrS-PRS has already shown potential for identifying individuals with conduction abnormalities in the general population. Interestingly, genetic variants linked to BrS appear protective against atrial fibrillation, a common arrhythmia.
Beyond the Project's Scope
NaV1.5-CARED will develop hiPSC-derived cardiomyocyte models for high-throughput analysis of NaV1.5 expression, localization, and sodium current density. These models could also be used to test drug safety, aligning with CiPA guidelines for assessing proarrhythmic risks.
The progress of the NaV1.5-CARED project during these first 12 months, aligns with the planification of the deliverables and milestones presented in the initial Gantt chart. Two articles and two reviews related to NaV1.5-CARED have been published. Two additional articles are under review or in preparation. Furthermore, the deposit of six patents is considered.
As planned, several tasks started in parallel, such as with the harmonization of existing clinical databases (WP1: Partner INSERM, CHUN & AMC) constituting the largest worldwide patient database presenting the Brugada syndrome, an inherited electrical cardiac disease at risk of sudden cardiac death. The achievement of this task allowed us to publish a first clinical study on long-term prognosis of patients with an SCN5A mutation presenting progressive cardiac conduction disorder or Brugada syndrome.
In line with WP2 objectives, additional samples from collaborative centers and new participating centers have been identified to reach a patient population of about 6 000 cases. To anticipate the application of innovative genotyping technology and corresponding analysis planned in the WP2, pilot studies and bio-informatic tool comparisons have been led. To stick to the state of the art regarding the sequencing technology, an updated benchmark has been performed (partners INSERM & AMC) for the task 2.4.
A synergistic and collaborative effort has been led by partners INSERM, AMC, SMARTOX, PACU and MDC to reach the objective of WP3. From identified genomic regions involved in SCN5A expression regulation (one manuscript has been recently published and another is in preparation), we are developing new tools such as modified cell lines to characterize the role of these targets on SCN5A regulation and NaV1.5 expression at the membrane as well as the impact of new therapies developed by partners PACU (manuscript under review), SMARTOX & MDC in the context of the WP4.
As planned, several tasks started in parallel, such as with the harmonization of existing clinical databases (WP1: Partner INSERM, CHUN & AMC) constituting the largest worldwide patient database presenting the Brugada syndrome, an inherited electrical cardiac disease at risk of sudden cardiac death. The achievement of this task allowed us to publish a first clinical study on long-term prognosis of patients with an SCN5A mutation presenting progressive cardiac conduction disorder or Brugada syndrome.
In line with WP2 objectives, additional samples from collaborative centers and new participating centers have been identified to reach a patient population of about 6 000 cases. To anticipate the application of innovative genotyping technology and corresponding analysis planned in the WP2, pilot studies and bio-informatic tool comparisons have been led. To stick to the state of the art regarding the sequencing technology, an updated benchmark has been performed (partners INSERM & AMC) for the task 2.4.
A synergistic and collaborative effort has been led by partners INSERM, AMC, SMARTOX, PACU and MDC to reach the objective of WP3. From identified genomic regions involved in SCN5A expression regulation (one manuscript has been recently published and another is in preparation), we are developing new tools such as modified cell lines to characterize the role of these targets on SCN5A regulation and NaV1.5 expression at the membrane as well as the impact of new therapies developed by partners PACU (manuscript under review), SMARTOX & MDC in the context of the WP4.
WP1: Integrated datasets now include ~80 clinical parameters for BrS patients. A manuscript on long-term prognosis for SCN5A mutation carriers has been published.
WP2: A pipeline was established to map genetic variants linked to SCN5A regulation. An upstream enhancer deletion reduced sodium current by 50%, highlighting its therapeutic potential.
WP3: AAV6-mediated CRISPRi delivery showed high transduction efficiency, effectively suppressing target gene expression.
WP4: S10s therapy increased sodium current in patient-derived cells and improved conduction in a mouse model. Novel AAV vectors optimized for cardiac delivery outperformed standard variants.
WP2: A pipeline was established to map genetic variants linked to SCN5A regulation. An upstream enhancer deletion reduced sodium current by 50%, highlighting its therapeutic potential.
WP3: AAV6-mediated CRISPRi delivery showed high transduction efficiency, effectively suppressing target gene expression.
WP4: S10s therapy increased sodium current in patient-derived cells and improved conduction in a mouse model. Novel AAV vectors optimized for cardiac delivery outperformed standard variants.