DNA enzyme targeting TNF-alpha mRNA improves hemodynamic performance in rats with postinfarction heart failure

Tumor necrosis factor-alpha (TNF-alpha) probably affects the pathogenesis o f heart failure. Here we have investigated the therapeutic potential of a n uclease-resistant DNA enzyme that specifically cleaves TNF-alpha mRNA. A ph osphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TN F-alpha in vitro. To test its efficacy in vivo, postinfarction congestive h eart failure was induced in anesthetized rats by ligation of the left coron ary artery. A 4-wk treatment with the DNA enzyme induced a substantial redu ction in left ventricular end-diastolic pressure and lung weight concomitan t with an increase in arterial blood pressure and myocardial blood flow com pared with controls. The concentration of TNF-alpha in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-alpha mRNA was subst antially reduced. Recovery studies showed that the DNA enzyme cleavage acti vity was present within the myocardium throughout the observation period an d had no apparent toxic effects. Our findings indicate that DNA enzyme-base d therapy may hold promise in the treatment of this debilitating disease.