Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing Toll-Like Receptors (TLR3, 7, 8 and 9). The inappropriate activation of these TLRs can engender a variety of inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE), sepsis, Alzheimer s disease, inflammatory bowel disease, psoriasis, multiple sclerosis and rheumatoid arthritis. The redundancy of the nucleic acid-sensing TLR family suggests that biomaterials that can neutralize the proinflammatory effects of any nucleic acid regardless of its sequence, structure or chemistry would be useful anti-inflammatory agents. Herein we propose to explore a novel approach to anti-inflammatory drug design and assess whether certain nucleic acid-binding polymers can inhibit activation of all nucleic acid-sensing TLRs and thus act as potent anti-inflammatory agents. As an initial disease model we will test the therapeutic efficacy of such agents in a murine model of SLE. Successful completion of these studies will yield a novel, safer strategy as well as lead therapeutic agents to treat SLE and other inflammatory diseases that afflict millions of Americans and patients throughout the world. Thus these studies are greatly needed and highly clinically significant.
Uncontrolled activation of nucleic acid-sensing Toll-like receptors is involved in pathogenesis of systemic lupus erythematosus (SLE). In this grant application, we propose to develop a universal drug that will neutralize the ability of nucleic acids to stimulate nucleic acid-sensing TLRs. Successful completion of these studies will set the stage for the clinical development of a new class of safe and effective anti-inflammatory drugs for patients with SLE.
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