# Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $516,609

## Abstract

Summary
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. Despite the progress in unraveling
the genetic basis of DCM, there is a lack of disease-modifying therapies that target the underlying genetic
etiology. In preliminary studies, we identified the transcription factor 4 (ATF4) as a potential target for therapeutic
interventions in genetic DCM. ATF4 is a critical factor mediating the integrated stress response; an adaptive
pathway activated in response to stress. ATF4 is selectively translated in response to specific forms of cellular
stress to induce the expression of genes involved in adaptation to stress. Here we propose a multidisciplinary
approach to explore the potential role of ATF4-mediated regulation of one-carbon metabolism in cardiac
physiology and develop novel mutation-agnostic gene therapy for DCM. In Aim 1, we will test whether ATF4
overexpression can rescue the contractility deficit, a hallmark of DCM, in a mutation-agnostic manner using
iPSC-CMs derived for patients carrying DCM-causing mutation in diverse gene ontologies. In Aim 2, we will
examine the potential role of ATF4-mediated regulation of one-carbon metabolism gene expression in
cardiomyocyte function. In Aim 3, we will use AAV-mediated overexpression of ATF4 in vivo and test whether
ATF4 signaling could reverse or halt the progression of DCM in vivo. Unlike conventional gene therapies, our
approach does not replace a faulty or missing gene. Instead, our approach aims at triggering a cardioprotective
effect by bolstering the ATF4-dependent one-carbon metabolism gene expression in the heart. We hope to
provide proof-of-concept for a new clinically relevant therapeutic strategy, paving the way for mutation-agnostic
treatments for genetic DCM. Such treatments are likely to apply to other types of cardiac diseases such as heart
failure.

## Key facts

- **NIH application ID:** 10586652
- **Project number:** 2R01HL139679-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ioannis Karakikes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $516,609
- **Award type:** 2
- **Project period:** 2018-07-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586652

## Citation

> US National Institutes of Health, RePORTER application 10586652, Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine (2R01HL139679-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10586652. Licensed CC0.

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