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Tadalafil/Sildenafil Study for muscle and heart function in DMD

Dr. Ron Victor, Cedars Sinai Medical Center

  • Funding Type: PPMD Investigator Award
  • Amount: $753,625
  • Date: 4/2011 - 3/2013
  • Title: DMD Tadalafil and Sildenafil Titration Protocol Research Grant

Major New Hypothesis

PDE5A inhibition, which boosts NO-cGMP signaling, will relieve functional muscle ischemia and restore normal blood flow regulation (i.e., functional sympatholysis) during exercise in boys with DMD. Our specific aim is to perform an efficient dose-titration study to inform the design of a randomized multi-center trial of PDE5A inhibition for clinical skeletal muscle and cardiac endpoints.

Abstract

Duchenne and Becker muscular dystrophies (DMD, BMD) are congenital X-linked muscle wasting diseases leading to shortened median life expectancies of 20 years in patients with DMD and of 50 years in patients with BMD. Two decades have passed since dystrophin was found to be the disease-causing gene in both conditions. Despite this knowledge and an explosion of basic research using elegant mouse models, clinical research has not kept pace and we still have no specific treatment for these patients. Our previous work—parallel translational experiments in mouse models and patients with muscle diseases including DMD—showed that loss of sarcolemmal nitric oxide synthase (nNOS), a dystrophin-associated protein, renders the diseased muscle fibers susceptible to functional ischemia and implicated skeletal muscle-derived nitric oxide (NO) as a novel therapeutic target for these refractory conditions. Specifically, we showed that skeletal muscle derived NO normally modulates adrenergic vasoconstriction in exercising skeletal muscle, a protective mechanism (“functional sympatholysis”), which is defective in the mdx mouse, the nNOS null mouse, and boys with DMD leading to functional muscle ischemia. Subsequently, several groups have shown that genetic and pharmacologic strategies that enhance NO signaling can ameliorate many features of the dystrophic phenotype—at least in mice, zebra fish, and drosophila. Recently, in the mouse model of DMD/BMD, acute administration of phosphodiesterase (PDE5A) inhibitors, which prolong the half-life of cGMP—the downstream target of NO in vascular smooth muscle—ameliorated muscle ischemia, muscle edema, and muscle fatigue after an acute bout of exercise. However, the dose of the PDE5A inhibitor in the mouse experiments was huge, and a key question is whether a clinical dose will be effective. We now propose parallel translational experiments in boys with DMD.

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