Blocking Toll-Like Receptor Pathway Using an Antagonist of TLR7, 8 and 9 Reduces Inflammation in Dystrophin Deficient mdx Mice (PD3.004)

OBJECTIVE: The aim of this study was to evaluate the effect of an antagonist of Toll-like receptors (TLRs) 7, 8 and 9 in modulating disease phenotype in dystrophin deficient mdx mouse model of Duchenne muscular dystrophy (DMD).BACKGROUND: DMD is a lethal, progressive genetic muscle disease for which there is no treatment. Prednisone is the standard of care for DMD but has significant adverse effects upon chronic use. We have previously shown that inflammation and TLR activation is seen very early in the DMD patients (Chen et al., Neurology, 2005). We performed proof of concept experiments to evaluate efficacy of a TLR7/8/9 antagonist to reduce inflammation in the mdx mouse model of DMD.DESIGN/METHODS: At 5 weeks of age, male mdx mice were treated with vehicle, 2.5, 5 or 10 mg/kg of TLR7/8/9 antagonist twice a week via IP injection. Untreated age matched BL10 mice were used as normal controls. Functional, behavioral and histological measurements were assessed after 4 weeks of treatment.RESULTS: In vivo optical imaging and histology (H&E) of skeletal muscle showed a significant reduction in inflammation in antagonist-treated groups compared to vehicle group. Creatine kinase levels were also significantly decreased in treated groups. There was a small dose dependent increase in EDL specific force in treated groups. No significant differences were found in grip strength and open field digiscan behavior measures in this 4-wk treatment regimen. No changes in body weights of treated mdx mice were found.CONCLUSIONS: These findings support that targeting TLR7/9 pathway using TLR antagonists in dystrophin deficient muscle reduces inflammation. Since it is a selective TLR antagonist it is likely to be a safer therapeutic option than glucocorticoids for DMD patients.Disclosure: Dr. Yu has nothing to disclose. Dr. Huynh has nothing to disclose. Dr. Sali has nothing to disclose. Dr. Creeden has nothing to disclose. Dr. Quinn has nothing to disclose. Dr. Vandermeulen has nothing to disclose. Dr. Spurney has nothing to disclose. Mr. Kandimalla is a full time employee of Idera pharmaceuticals, Inc. Dr. Agrawal has received personal compensation for activities with Idera Pharmaceuticals, Inc as an employee. Dr. Nagaraju has nothing to disclose.