Perm1 Gene Therapy Mitigates PRDM16-Associated Cardiomyopathy.

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Pathogenic variants in PRDM16 cause cardiomyopathies with impaired metabolic maturation.
• PRDM16 deficiency alters cardiac fatty acid metabolism, but downstream mediators are unclear.
• The potential of improving mitochondrial fatty acid metabolism to prevent PRDM16 cardiomyopathy is unknown.

Purpose of the Study:

• To identify downstream mediators of PRDM16 in cardiac fatty acid metabolism.
• To investigate if enhancing mitochondrial fatty acid metabolism can prevent PRDM16-associated cardiomyopathy.

Main Methods:

• Utilized patient-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and Prdm16 knockout mouse models.
• Performed transcriptomics, proteomics, and adeno-associated virus (AAV)-mediated gene therapy.
• Investigated the role of PERM1 as a downstream target of PRDM16.

Main Results:

• Defects in fatty acid metabolism are an early sign of PRDM16 cardiac deficiency.
• PERM1 is a direct downstream target of PRDM16, regulating fatty acid metabolism with PGC1α.
• Neonatal AAV9-Perm1 gene therapy in Prdm16 cKO mice improved cardiac function, reduced dilation, and extended survival, independent of restoring FA oxidation.
• Gene therapy preserved mitochondrial structure, sarcomere organization, and reduced cardiac remodeling.

Conclusions:

• Identified a PRDM16-PGC1α-PERM1 axis crucial for cardiac fatty acid metabolism.
• Perm1 gene therapy ameliorated cardiomyopathy by preserving mitochondrial and sarcomere integrity.
• Perm1 gene therapy represents a potential therapeutic strategy for PRDM16-associated cardiomyopathy.