Abstract/Statement of Work Previous studies from our laboratories have indicated that nucleic acid binding polymers (NABPs), also termed nuclear acid scavengers (NASs), can inhibit immune responses induced by nucleic acids in both acute and chronic models in lupus prone mice. While these studies indicate the potential utility of NASs as a therapy for lupus, many aspects of their pharmacologic properties are less than ideal. Therefore, to advance this novel approach, we will utilize cutting edge bioengineering strategies to create novel, biocompatible NABPs for in vivo use as nucleic acid scavengers. Finally, the proposed research will incorporate studies with lupus patient material as well as animal models to address fundamental issues on nucleic acid DAMP (Damage Associated Molecular Pattern) responses, identify novel biomarkers for disease progression and classification and elucidate the mechanism(s) by which NABPs sequester and scavenge nucleic acids to prevent (or disrupt) the formation of immune complexes and thereby reduce the pathogenic potential of such DAMPs. Three specific aims are proposed: Aim #1: To rationally engineer biocompatible, nucleic acid scavengers with optimized binding to nucleic acid-containing DAMPs and associated DAMP complexes. Aim #2: To evaluate the therapeutic efficacy, safety, biodistribution and biocompatibility of soluble and nanoparticle containing nucleic acid scavengers in mouse models of lupus that display renal, cutaneous and arthritic manifestations. Aim #3: To elucidate the mechanism(s) by which nucleic acid scavengers counteract the ability of nucleic acid-containing DAMPs to activate inflammatory cells in mice and in patient samples. Successful completion of the studies proposed will set the stage for the clinical development of a novel class of safe and potent anti-inflammatory agents for lupus and lupus-arthritis patients.

Project Narrative Engineering Polymers to Scavenge DAMPs in Lupus and Lupus Arthritis Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be recognized as Damage Associated  Molecular Patterns (DAMPs) and taken up by inflammatory cells and activate multiple nucleic acid-­‐sensing Toll-­‐Like  Receptors (TLR3, 7, 8 and 9) and other pattern recognition receptors (PRRs). The inappropriate activation of these TLRs  and PRRs can engender a variety of inflammatory and autoimmune diseases including systemic lupus erythematosus  (SLE) and rheumatoid arthritis (RA). The redundancy of the nucleic acid-­‐sensing TLR/PRR 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. We have preformed preliminary studies indicating that such  “nucleic acid scavengers” can reduce inflammation in animal models of SLE and RA. Herein we propose to explore in  detail this novel approach to anti-­‐inflammatory drug design. We will evaluate the ability of this approach to limit lupus  and lupus arthritis patient samples from activating of innate inflammatory cells in vitro and employ biomedical  engineering to create potent and safe agents to scavenge nucleic acid-­‐containing in animal models. We will test the  therapeutic efficacy of such agents in a murine model of SLE and Lupus Arthritis. 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.