Project Grant R43AR082791

NOVEL THERAPY FOR ARTHROFIBROSIS - NOVEL THERAPY FOR ARTHROFIBROSIS ABSTRACT ARTHROFIBROSIS (AF) IS A COMMON RESULT OF JOINT SURGERIES. THE FORMATION OF COLLAGEN-RICH FIBROTIC SCARS IS UNCONDITIONALLY NECESSARY FOR AF AND SUGGESTS AN EFFECTIVE THERAPEUTIC APPROACH. COLLAGEN FIBRILS ARE FORMED IN THE EXTRACELLULAR SPACE BY AGGREGATION OF INDIVIDUAL COLLAGEN I MOLECULES (MONOMERS) PRODUCED BY CELLS IN RESPONSE TO INJURY. THE ASSEMBLY OF COLLAGEN I MOLECULES INTO FIBRILS DEPENDS ON THE BINDING INTERACTION BETWEEN THE VERY ENDS, I.E., TELOPEPTIDES, OF ONE COLLAGEN MOLECULE AND THE TELOPEPTIDE BINDING REGION (TBR) OF AN INTERACTING PARTNER. BLOCKING THE C-TERMINAL TELOPEPTIDE OF THE A2(I) CHAIN OF COLLAGEN I A2(I)CT WITH AN ANTI-A2(I)CT ANTIBODY (REFERRED TO AS ACA, ANTI-COLLAGEN ANTIBODY) INHIBITS MONOMER-MONOMER INTERACTION, THEREBY INHIBITING COLLAGEN FIBRIL FORMATION AND REDUCING UNWANTED SCARRING. WHILE FIBRIL-INCORPORATED COLLAGEN I MOLECULES ARE STABLE IN VIVO, FREE COLLAGEN MOLECULES THAT ARE NOT PART OF THE FIBRILS (E.G., DUE TO BLOCKING WITH THE ACA) ARE NOT STABLE AND THEREFORE UNDERGO DEGRADATION. THE EXTENT OF THE INHIBITION OF COLLAGEN FIBRIL FORMATION IS ACA-CONCENTRATION DEPENDENT. THUS, REDUCING THE EXCESS OF COLLAGEN-RICH DEPOSITS AND BLOCKING ONLY A FRACTION OF ALL PRODUCED COLLAGEN I MOLECULES STILL ALLOWS COLLAGEN FIBRILS TO BE FORMED AND ENABLES EFFECTIVE HEALING. OUR IN VIVO STUDIES IN A RABBIT MODEL OF POSTTRAUMATIC JOINT STIFFNESS SHOWED NO ADVERSE EFFECTS OF THE ACA. FOR POTENTIAL CLINICAL USE, WE HAVE HUMANIZED THE ACA. DURING THIS PHASE I PROJECT, WE WILL IMPROVE DELIVERY AND TISSUE RESIDENCE BY LINKING A COLLAGEN-BINDING PEPTIDE (CBP) TO OUR LEAD HUMANIZED ACA. THE CBP DOMAIN WILL TARGET THE ANTIBODY TO SITES OF ONGOING COLLAGEN FIBRIL FORMATION. GRADUAL RELEASE FROM COLLAGEN IN AFFECTED REGIONS THAT SYNTHESIZE A2(I)CT WILL FACILITATE LONG-TERM TREATMENT, ENABLING THE ACA TO INHIBIT ONGOING FIBROSIS. WE WILL CHARACTERIZE THE CONSTRUCT IN VITRO TO ENSURE THE REQUIRED BINDING AND DEVELOPABILITY AND BEGIN IN VIVO EVALUATION IN A MODEL OF AF. PHASE 2 WORK WILL FURTHER EVALUATE ACA-CBP IN ADDITIONAL ANIMAL MODELS OF AF AND BEGIN IND-ENABLING PRECLINICAL STUDIES.