/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.
Engineering Polymers to Scavenge DAMPs in Lupus and Lupus Arthritis Deadanddyingcellsreleasenucleicacids.TheseextracellularRNAsandDNAscanberecognizedasDamageAssociated MolecularPatterns(DAMPs)andtakenupbyinflammatorycellsandactivatemultiplenucleicacid-?sensingToll-?Like Receptors(TLR3,7,8and9)andotherpatternrecognitionreceptors(PRRs).TheinappropriateactivationoftheseTLRs andPRRscanengenderavarietyofinflammatoryandautoimmunediseasesincludingsystemiclupuserythematosus (SLE)andrheumatoidarthritis(RA).Theredundancyofthenucleicacid-?sensingTLR/PRRfamilysuggeststhat biomaterialsthatcanneutralizetheproinflammatoryeffectsofanynucleicacidregardlessofitssequence,structureor chemistrywouldbeusefulanti-?inflammatoryagents.Wehavepreformedpreliminarystudiesindicatingthatsuch ?nucleicacidscavengers?canreduceinflammationinanimalmodelsofSLEandRA.Hereinweproposetoexplorein detailthisnovelapproachtoanti-?inflammatorydrugdesign.Wewillevaluatetheabilityofthisapproachtolimitlupus andlupusarthritispatientsamplesfromactivatingofinnateinflammatorycellsinvitroandemploybiomedical engineeringtocreatepotentandsafeagentstoscavengenucleicacid-?containinginanimalmodels.Wewilltestthe therapeuticefficacyofsuchagentsinamurinemodelofSLEandLupusArthritis.Successfulcompletionofthesestudies willyieldanovel,saferstrategyaswellasleadtherapeuticagentstotreatSLEandotherinflammatorydiseasesthat afflictmillionsofAmericansandpatientsthroughouttheworld.Thusthesestudiesaregreatlyneededandhighly clinicallysignificant.