NaV1.5 regulation fine-tuning as a therapy for cardiac Conduction and Arrhythmic diseases at Risk of suddEn Death

Project Information

NaV1.5-CARED

Grant agreement ID: 101115295

DOI

10.3030/101115295

EC signature date 21 June 2023

Start date 1 October 2023

End date 30 September 2028

Funded under

• The European Innovation Council (EIC)

Total cost

€ 4 892 256,25

EU contribution

€ 4 892 256,25

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - NaV1.5-CARED (NaV1.5 regulation fine-tuning as a therapy for cardiac Conduction and Arrhythmic diseases at Risk of suddEn Death)

Reporting period: 2024-10-01 to 2026-01-31

Summary of the context and overall objectives of the project

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 arrhythmia.
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 arrhythmia 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 prior application on pre-clinical models.


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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The progress of the NaV1.5-CARED project aligns with the scientific objectives defined in our initial work plan. Eight scientific articles resulting from NaV1.5-CARED discoveries have been published and four additional manuscripts are in preparation. Furthermore, five patents have been filed already.

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. At this stage, 3026 patient cases have been fully processed and passed quality control.

In line with WP2 objectives, additional samples from collaborative centers and new participating centers have been identified to reach a patient population of about 1500 WGS cases. So far, 850 cases have been processed. To anticipate the application of bioinformatic pipelines planned in the WP2 at the whole genome scale, pilot studies and bio-informatic tool comparisons have been led on the SCN5A and SCN10A locus. From this preliminary work, a first manuscript is in preparation highlighting the high potential of this analysis at the genome scale. To stick to the state of the art regarding the sequencing technology, an updated benchmark on the long-read sequencing technology has been performed (partners INSERM & AMC) for the task 2.4: a new approach from Illumina will be tested in the coming months (https://www.illumina.com/products/by-type/sequencing-kits/library-prep-kits/illumina-trupath-genome.html).

To characterize the role of genomic regions involved in SCN5A expression regulation, first cell-lines have been generated and validated for high-throughput screening.
A non viral cardiac-specific vector has been tested and may represent a relevant candidate for SCN5A expression modulation.
FNUSA-ICRC joined the consortium in September 2025 with the aim to further develop and use the Traction Force Microscopy to measure contractile force of iPSCs developed by AUMC and MDC partners. Pending the validation of these cell-lines, FNUSA-ICRC started working on several aspects of their techniques to be optimized.

As part of WP4 developments, PaCu have made relevant progress on miniaturizing constructs and AAV vectors able to restore NaV1.5 loss of function (new patent filed). This new innovative therapeutic tool is under investigation on Brugada Syndrome models by INSERM partner.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

WP1: 3026 Brugada Syndrome cases have been fully clinically harmonized in the REDcap database.

WP2: 850 cases have been whole-genome sequenced and corresponding analysis have been initiated and suggest high potential for new discovery.

WP3: First cell-lines have been generated and validated for high-throughput screening to identify genomic regions involved in SCN5A expression regulation.

WP4: Constructs have been miniaturized and AAV vectors optimized in order to improve safety issue and therapeutic efficacy.