PERM1, a new therapeutic target for PRDM16-associated cardiomyopathy

About This Grant

Summary PRDM16-associated cardiomyopathy manifests in individuals with 1p36 deletion syndrome (1p36DS) and in patients harboring de novo mutations in the PRDM16 gene. We recently demonstrated that PRDM16 loss in 1p36DS is directly responsible for the development of left ventricular non-compaction (NCM) and dilated cardiomyopathy (DCM). Notably, female patients with PRDM16 loss exhibit earlier onset DCM and worse clinical outcomes compared to their male counterparts. Consistent with these clinical observations, cardiac-specific PRDM16 deficiency in mice leads to early-onset DCM and reduced survival in females. The molecular basis for this sex-specific vulnerability, however, remains unclear. Although recent studies, including our own, have advanced understanding of PRDM16’s role in cardiac development and metabolism, there are currently no effective therapies for PRDM16-associated DCM. Individuals with 1p36DS or PRDM16 loss-of-function variants are increasingly diagnosed yet face reduced survival and limited treatment options—particularly females. This underscores the urgent need for targeted therapies and early intervention strategies tailored to this high-risk population. This proposal aims to: 1) uncover female-specific molecular mechanisms driving PRDM16-associated DCM; 2) establish a global, multi-institutional registry of PRDM16 variant carriers and generate induced pluripotent stem cells (iPSCs) to explore sex-specific disease pathways; and 3) validate the role of peroxisome proliferator- activated receptor gamma coactivator 1 (PPARGC1) and estrogen-related receptor (ERR)-regulated PERM1 as therapeutic targets. Aim 1 will elucidate the sex-specific drivers of disease, while Aim 2 will assess the therapeutic potential of PERM1 in this context. By identifying and validating molecular targets, this research aims to improve outcomes for patients with PRDM16 deletion, both within and beyond the context of 1p36DS. A focus on female-specific mechanisms may inform precision medicine strategies for at-risk women, and broader insights into sex-biased cardiac dysfunction. Our translational approach holds promise to significantly impact clinical care, enhancing both survival and quality of life for affected individuals.