CAMBRIDGE, Mass. & HACKENSACK, N.J.—Idera Pharmaceuticals and Parent Project Muscular Dystrophy (PPMD) will collaborate to advance Idera's proprietary Toll-like receptor (TLR) technology for the treatment of Duchenne muscular dystrophy (MD). The two organizations 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.
"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, Ph.D., CEO 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, damaged and dying 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-alpha.
"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, has 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.
Duchenne is a fatal genetic disorder that slowly robs young men of their muscle strength. Parent Project Muscular Dystrophy (PPMD) is the largest, most comprehensive nonprofit organization in the U.S. focused on finding a cure for Duchenne muscular dystrophy.
PPMD invests deeply in treatments for this generation of young men affected by Duchenne and in research that will benefit future generations. PPMD advocates in Washington, D.C., and has secured hundreds of millions of dollars in funding. PPMD demands optimal care, and strengthens, unites and educates the global Duchenne community.
Children's National Health System, based in Washington, D.C., has been serving the nation's children since 1870. Children's National is Magnet® designated and is consistently ranked among the top pediatric hospitals by U.S. News & World Report. Home to the Children's Research Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National is one of the nation's top NIH-funded pediatric institutions. With a community-based pediatric network, seven regional outpatient centers, an ambulatory surgery center, two emergency rooms, an acute care hospital and collaborations throughout the region, Children's National is recognized for its expertise and innovation in pediatric care and as an advocate for all children.
Idera Pharmaceuticals is a clinical-stage biopharmaceutical company developing a novel therapeutic approach for the treatment of genetically defined forms of B-cell lymphoma and rare diseases. Idera's proprietary technology involves creating novel nucleic acid therapeutics designed to inhibit over-activation of Toll-like Receptors. In addition to its TLR programs, Idera is developing gene silencing oligonucleotides that it has created using its proprietary technology to inhibit the production of disease-associated proteins by targeting RNA.