Studies Confirm Benefits of
Blocking Inflammation in DMD

A research group headed by MDA grantee Denis Guttridge at Ohio State University Medical Center in Columbus has significantly added to knowledge of how inflammation and inhibition of muscle formation are involved in Duchenne muscular dystrophy (DMD). Their data support the validity of existing therapies, such as corticosteroids, and suggest additional pathways to pursue in new therapy development.

Swarnali Acharyya at Ohio State, with colleagues there and at several other institutions, published their findings online March 22 in the Journal of Clinical Investigation.

They report that a signaling pathway called IKK/NF-kappa-B, which markedly increases the inflammatory response of the immune system and inhibits muscle regeneration, is abnormally active in mice lacking dystrophin. These mice have a muscle disease that resembles human DMD, in which the dystrophin protein is also missing.

When the investigators treated the mice with NBD, a compound that blocks the activation of the IKK/NF-kappa-B pathway, the animals showed significantly less inflammation and more regeneration of muscle tissue. Their diaphragm muscles showed better force development than those of mice treated with an inactive form of this compound.

Corticosteroid drugs, such as prednisone, also interfere with inflammation by blocking NF-kappa-B. These medications, which help maintain muscle function in patients with DMD, have been in use in this disease for several years, although neither their mechanism nor their proper dosage level has been clear. (A multinational clinical trial, slated to begin soon, will answer some of the questions surrounding their use.)

“We’re excited about these findings, because we believe they add to our understanding of how this signaling pathway functions in muscle disorders such as DMD,” Guttridge said. “Based on our genetic and pharmacological data, it suggests that NF-kappa-B acts in both immune cells and muscle cells to regulate the dystrophic process.

“We believe this would make NF-kappa-B an attractive therapeutic target. Presumably, if you can inhibit its activity in both cell types, you should be able to block inflammation and at the same time stimulate new muscle growth.”

Guttridge says evidence from their work and other published studies demonstrates that NBD isn’t toxic in mice but that follow-up studies will be needed to confirm this before human trials can be contemplated.