Idera Pharmaceuticals, a Cambridge, Mass.-based clinical-stage biopharmaceutical company, and nonprofit organization Parent Project Muscular Dystrophy (PPMD), based in Hackensack, N.J., are collaborating to advance Idera's proprietary Toll-like receptor (TLR) technology for the treatment of Duchenne muscular dystrophy.
Idera and PPMD intend to work together to conduct preclinical studies and develop a clinical development strategy for an investigational TLR antagonist candidate.
In previous preclinical studies in models of Duchenne, treatment with a TLR antagonist candidate led to a reduction in disease-associated markers of inflammation and improved muscle function.
Duchenne is a rare, fatal neuromuscular disorder characterized by progressive muscle weakness, increasing disability limiting activities of daily living, pulmonary and cardiac dysfunction, and death typically before age 30. It affects approximately 15,000 to 20,000 patients in the U.S. and is caused by the lack of dystrophin, an essential protein that stabilizes the membranes of muscle cells.
Due to compromised cellular membranes, dying and damaged muscle cells release self RNA and other molecules which are recognized by the body's innate immune system as Damage Associated Molecular Patterns (DAMPs). In preclinical studies, researchers have shown that DAMPS stimulate TLR-mediated signaling pathways that trigger an inflammatory response. This TLR-mediated inflammatory response is believed to cause additional muscle cell damage, propagating a cycle of tissue damage that contributes to disease progression. TLRs represent novel targets in Duchenne upstream of other traditional inflammatory targets such as NF-KB and TNF-a.
Independent research published by investigators from Children's National Health System in Wash. D.C., have demonstrated the role of TLRs in the pathogenesis of DMD. Results from this study showed a statistically significant 6.6-fold over expression of TLR 7 in the muscle fibers of patients with Duchenne compared with healthy controls aged five to 12 years. In addition, investigators reported that TLR 7 also was over expressed in pre-symptomatic infants, suggesting TLR activation is an early trigger of muscle inflammation in Duchenne.
Additional preclinical research published by investigators from Children's National Health System and Idera showed that inhibition of TLR activity improved disease-associated measures in Duchenne models. To assess the potential utility of inhibiting TLR activity, investigators knocked out the gene for MYD88, an adaptor protein in the TLR signaling pathway, and evaluated muscle function in the mdx mouse model of Duchenne. Results showed statistically significant improvements in skeletal and cardiac muscle function.