In a recent publication Nelson et al proposed to use PDE5 inhibitors to treat DMD.

Duchenne Muscular Dystrophy (DMD) is a fatal progressive disease that affects about one in 3500 boys. DMD is caused by mutations in dystrophin that yield to protein loss. As a result, DMD myofibers are more susceptible to contraction-induced injury, leading to multiple cycles of muscle degeneration and regeneration and muscle fibrosis. Although great progress has been made toward the identification of new therapies for DMD, only glucocorticoids, such as prednisone and deflazacort, are currently approved, and have been shown to result in some benefit for DMD patients.

Multiple promising therapeutic approaches for DMD that had great efficacy in cell culture and animal models sadly fell short during clinical trials. Preclinical data on DMD has yet to translate into the clinic. A possible new avenue for treatment of DMD comes from a totally different angle. Phosphodiesterase type 5 (PDE5) inhibitors that are generally used to treat erectile dysfunction and pulmonary hypertension, were first demonstrated to improve the skeletal muscle and cardiac phenotypes in the dystrophin KO mice mdx. Furthermore, Martin et al proved that the PDE5 inhibitor taladafil alleviates muscle ischemia in patients with Becker Muscular Dystrophy.

The same group commanded by Ronald G. Victor has just reported that PDE5 inhibition also alleviates exercise-induced skeletal muscle ischemia in DMD boys. The authors demonstrated that pediatric patients with DMD present impaired sympatholysis (sympathetic vasoconstriction) after exercise that leads to functional muscle ischemia, despite background therapy with corticosteroids. Importantly, the authors showed that the PDE5 inhibitors taladafil and sildenafil alleviate muscle ischemia in patients with DMD in an immediate and dose dependent manner. The doses used correspond to the ones approved by FDA to treat erectile dysfunction and pediatric pulmonary hypertension.

The authors hypothesized that PDE5 inhibition boosts a residual nitric oxide-cGMP signal arising from cytosolic neuronal Nitric Oxide Synthase (NOS), which, in the absence of dystrophin, is misplaced from the sarcolemma, in a mechanism that does not involve endothelial NOS-derived NO or central inhibition of sympathetic outflow.

Although it is still unknown whether the administration of PDE5 inhibitors will improve blood flow in the long term and if this will result in a milder or a slower progression of the disease, this report opens a new avenue for therapies against this devastating condition.