Idera, Parent Project Muscular Dystrophy partner to advance new treatment approach for duchenne muscular dystrophy

As part of this collaboration, 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.

Idera is a clinical-stage biopharmaceutical company focused on developing nucleic acid therapeutics for patients with rare and serious diseases. PPMD is the largest and most comprehensive nonprofit organization in the U.S. focused on finding a cure for Duchenne.

"We look forward to partnering with Idera Pharmaceuticals, a leader in the development of nucleic acid therapeutics for rare diseases, to advance a novel approach to controlling muscle inflammation with the potential to treat all patients regardless of their genetic mutation," said Pat Furlong, Founding President and CEO of PPMD.

"One of our organization’s primary objectives is to advance potential treatments so that all people with Duchenne have an opportunity to live longer and fuller lives. For 20 years, we have done whatever we can to support new and promising technologies. PPMD looks forward to working with Idera on this new area of biology to advance treatments applicable to all patients."

"We are very pleased to work with PPMD on advancing the potential application of TLR antagonism to address the underlying inflammation that propagates disease progression in Duchenne. PPMD brings decades of experience working with families affected by Duchenne, as well as close ties with scientists and clinicians working in the field worldwide," said Sudhir Agrawal, D.Phil., Chief Executive Officer of Idera Pharmaceuticals.

"We look forward to collaborating with PPMD and researchers from Children’s National Health System, to conduct preclinical studies to inform a clinical development strategy."

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 United States 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.

"Over the last five years, we have demonstrated in preclinical studies that TLRs play a critical role in triggering inflammation in neuromuscular diseases such as Duchenne. Based on this research, we believe there is a clear scientific rationale for the evaluation of TLR antagonism as a potential treatment approach," said Kanneboyina Nagaraju, Ph.D., DVM, Professor of Integrative Systems Biology and Pediatrics at the George Washington University School of Medicine and Health Sciences and Children’s National Health System.

Independent research published by investigators from Children’s National Health System in Washington, DC, 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 5 to 12 years.

In addition, investigators reported that TLR 7 was also 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. In a separate experiment, mdx mice treated with an antagonist of TLR 7 and TLR 9 showed significant reductions in muscle inflammation and creatine kinase, a marker of muscle damage, and increased muscle force.