Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for -Associated Cardiac Defects in Mice.

The truncating mutations of are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for -associated cardiac defects.