Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy

Rouzbehani, O. M.; Stephens, S. L.; Werbner, B.; Szulik, M. W.; Bo, S.; Hua, M.; Watanabe, S.; Leonelli, A.; Goodman, M.; Bia, R.; Davey, C.; Golkowski, M.; Franklin, S.; Landstrom, A. P.; Boudina, S.

doi:10.64898/2026.04.13.718330

bioRxiv · 10.64898/2026.04.13.718330

Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy

Rouzbehani, O. M.·Stephens, S. L.·Werbner, B.·Szulik, M. W.·Bo, S.·Hua, M.·Watanabe, S.·Leonelli, A.·Goodman, M.·Bia, R.·Davey, C.·Golkowski, M.·Franklin, S.·Landstrom, A. P.·Boudina, S.

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Abstract

BackgroundPathogenic variants in PR domain containing 16 (PRDM16) cause pediatric and adult cardiomyopathies characterized by ventricular dilation, systolic dysfunction, and impaired metabolic maturation. Cardiac deficiency of PRDM16 alters metabolic gene expression and long-chain fatty acid (FA) metabolites. However, the downstream mediators involved are not well characterized. Furthermore, whether improving mitochondrial FA metabolism can prevent PRDM16-associated cardiomyopathy is currently unknown. MethodsIn vivo and in vitro approaches using patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse models with Prdm16 deletion/mutation were employed. Transcriptomics and proteomics analyses were conducted, and adeno-associated virus (AAV)-mediated therapy was tested. ResultsHere, we show that a defect in FA metabolism is an early hallmark of PRDM16 cardiac deficiency. We show, for the first time, that PERM1 is a direct downstream target of PRDM16 and is involved in the regulation of FA metabolism through coordinated action with PGC1. Most importantly, neonatal delivery of AAV9-Perm1 in cardiac-specific Prdm16 knockout (Prdm16 cKO) mice markedly improved contractile parameters, reduced left ventricular (LV) dilation, and extended survival. These cardioprotective effects of PERM1 gene therapy occurred independent of restoring FA oxidation. Transcriptional and proteomic analyses of AAV-Perm1-treated Prdm16 cKO mice demonstrated significant improvements in mitochondrial cristae architecture, preservation of sarcomere organization, reduced cardiomyocyte apoptosis, attenuated myocardial fibrosis, and diminished cardiac remodeling. ConclusionsWe identify PERM1 as a direct downstream effector of PRDM16 and uncover a previously unrecognized PRDM16-PGC1-PERM1 axis essential for FA metabolic regulation in the heart. Perm1 gene therapy ameliorated PRDM16-associated cardiomyopathy through post-transcriptional mechanisms involving preservation of mitochondrial and sarcomere integrity. The current study provides preclinical evidence suggesting that Perm1 gene therapy may be a promising therapeutic target to improve the cardiac outcomes of patients affected by pathogenic PRDM16 variants.

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Rouzbehani, O. M., Stephens, S. L., Werbner, B., Szulik, M. W., Bo, S., Hua, M., Watanabe, S., Leonelli, A., Goodman, M., Bia, R., Davey, C., Golkowski, M., Franklin, S., Landstrom, A. P., Boudina, S.. 2026-04-15. Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy. https://doi.org/10.64898/2026.04.13.718330

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