Gene Therapy with the N-terminus of Junctophilin-2 Improves Hypertrophy and Heart Failure in Mice

Our previous work found a variety of cardiac stresses initiate site-specific cleavage of junctophilin-2 (JP2), an essential component of the E-C coupling apparatus, producing a 75-kDa N-terminal fragment (JP2NT) which unexpectedly translocates into cardiomyocyte nuclei and functions as a transcriptional repressor. We also determined that transgenic overexpression of JP2NT in cardiomyocytes attenuates pressure-overload induced hypertrophy and heart failure by blunting the induction of maladaptive transcripts. To test whether JP2NT could be utilized by gene therapy approaches for treating heart failure, we developed cardiotropic adeno-associated GFP and JP2NT expressing viruses for testing in a preclinical model of heart failure. Our results show that the transcriptional and pathological changes from pressure overload can be reduced through viral expression of JP2NT once hypertrophy and heart failure has already begun. Overall design: Sham or trans-aortic constriction (TAC) surgery was performed on 9–10-week-old mice. After two weeks, echocardiography was performed to identify TAC operated mice with moderate cardiac dysfunction (ejection fractions 40-60%, n=30) and sham operated mice with normal function (n=10). Mice were further divided into two groups each for receiving AAV2/9 virus expressing either GFP or JP2NT (tail vein injection, 1x10E12 viral genomes, 100 ul). Heart tissue was collected 8 weeks after surgery for RNA analysis.