G.P.356 - Preclinical data for a novel Toll-like receptor antagonist in mdx mice support its clinical development as a potential treatment for disease-related muscle inflammation in Duchenne muscular dystrophy

Abstract

Immunologically triggered inflammatory processes play a central role in the pathogenesis of Duchenne muscular dystrophy (DMD). Toll-like receptors (TLRs) are key components of the innate immune system involved in regulating inflammation and adaptive immunity. Data have shown that TLR 7 is significantly over-expressed in DMD patients at all stages of the disease, suggesting TLR activation is an early trigger of muscle inflammation. Targeting of TLRs is a novel therapeutic approach for DMD that has the potential to reduce chronic muscle inflammation and slow disease progression across a broad patient population regardless of dystrophin mutation type. IMO-8400 is a novel oligonucleotide-based antagonist of TLRs 7, 8 and 9 that was generally well tolerated and demonstrated anti-inflammatory activity in patients with autoimmune disease. To evaluate in vivo activity in a DMD model, we conducted multiple studies in mdx mice. Across studies, treated mice received one of several TLR antagonist regimens by i.p. injection for 5 weeks, and were assessed on measures of muscle function, muscle histology, biochemical response, and cytokine gene expression. Treatment resulted in significant reductions in muscle inflammation, serum creatine kinase, and gene expression of IL-6. An increase in the specific force of isolated extensor digitorum longus muscle was also observed. Detailed results from these preclinical studies will be presented. DMD is a genetic neuromuscular disorder in which immunologically triggered inflammatory processes play a central role in disease pathogenesis. TLRs are key drivers of inflammation and are over-activated in DMD patients at all stages of the disease. A TLR antagonist improved disease-associated measures in mdx mice. Collectively, these data support advancing the TLR antagonist drug candidate IMO-8400 into clinical development as a potential non-steroidal anti-inflammatory treatment for DMD patients.