Hypoxia-inducible plasmid expressing both miSHP-1 and HO-1 for the treatment of ischemic disease.

Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Unfortunately, current pharmacological treatments for ischemic heart disease do not reliably prevent the remodeling of the left ventricle and the progression to heart failure. Gene therapy offers a novel means to directly treat the pathophysiology underlying the long-term complications of ischemic heart disease. To date, gene therapies directed at single molecular targets have not been successful in the treatment of ischemic heart disease. In this study, we describe a gene therapy combination for inhibiting cardiomyocyte apoptosis under hypoxic conditions. This gene therapy combination utilizes a hypoxia-inducible plasmid expressing both heme oxygenase-1 (HO-1) and the Src homology domain-2 containing tyrosine phosphatase-1 microRNA (miSHP-1): pEpo-SV-miSHP-HO-1. This novel gene therapy construct demonstrated an enhanced expression of HO-1, production of miSHP-1, down-regulation of SHP-1, and inhibition of cardiomyocyte apoptosis under hypoxic compared to normoxic conditions. These results suggest that pEpo-SV-miSHP-HO-1 may be a promising gene therapy combination construct for the clinical treatment of ischemic disease.