Click Chemistry for Immobilized Bone Morphogenetic Protein
Department of Health and Human Services
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Small Business Information
PO BOX 14650, RESEARCH TRIANGLE PARK, NC, -
Socially and Economically Disadvantaged:
AbstractDESCRIPTION (provided by applicant): Growth factors are potent signaling molecules, initiating essential cellular programs for differentiation, proliferation and survival. Only recently have large molecules like growth factors, been employed to enhance the efficacy and specificity of medical implant therapies. In particular, procedures that require native tissues to interact with an implanted material stand to benefit from inclusion of growth factors. A successful merger at the interface between technology and biology is generally predictive of subsequent therapeutic outcome. Affinergy Inc., has developed bifunctional peptide linkers, called interfacial biomaterials (IFBMs) that help promote biology at the critical interface between a synthetic and a biologi c. Attaching one peptide designed to bind a growth factor, to another peptide designed to bind a medical device, offers a simple and target-specific therapeutic strategy. In addition, our modular approach allows interchangeability of peptide halves , to p roduce a combinatorial array of potential bifunctional IFBMs. Currently we chemically synthesize our peptides as one continuous sequence. This approach presents significant challenges, as coupling efficiency of solid-phase peptide synthesis decreases drama tically as chain length approaches 30 residues. We proposed a Phase I study, exploring the use of [3 + 2] cycloaddition or click chemistry to prepare IFBMs. This method takes advantage of our modular approach and allows for higher total yields through th e coupling of shorter peptides (lt25 mers). Additionally, selective coupling in the presence of unprotected amino acid side chains enables high-throughput screening capabilities of completed IFBM libraries. We have generated two IFBMs which bind a resorbab le collagen sponge and a bone morphogenetic protein (BMP); one using click chemistry and one using traditional solid-phase synthesis. In our Phase I studies, we found nearly identical biostability and in vitro activity of IFBMs made with both synthesis tec hniques. Successful completion of these aims has encouraged us to expand our IFBM technology to other growth factors and bone graft materials. Our goal in Phase II is to optimize click chemistry for IFBM manufacturing, examine the biocompatibility, storage , and sterilization of prototype IFBMs, and test their efficacy in vivo. Affinergy's IFBM technology is designed to improve growth factor therapy in three potential ways: 1) promoting the sustained release of BMP from existing carriers; 2) reducing the sup raphysiological amounts of recombinant growth factor required to provide the desired therapeutic effect and 2) capturing and concentrating endogenous molecules from the extracellular milieu, potential decreasing or eliminating the requirement for recombina nt protein.Project Narrative Bone grafts currently take one of three forms, which include autograft (typically harvested from the patient's iliac crest) allograft (cadaveric bone) and synthetics (helistat sponge, hydroxyapatite or tricalcium phosph ate). Autografts harbor all the endogenous biological capacity for bone regeneration, but represent a painful additional surgical step. Allograft and synthetics require no such secondary procedure, but have limited or no osteoinductive capabilities. Our go al is to therefore merge the benefits of both grafts, by adding a growth factor binding peptide coating to collagen-based bone grafts. We envision this technology as a means of reducing the dosage of expensive growth factors, while removing the pain and po tential complications associated with bone harvesting. This technology is likely most applicable to intervertebral and posterior lateral spinal fusion, procedures growing in frequency and known to benefit from osteoinductive growth factors. With over 45,00 0 spinal fusion surgeries performed each year, the demand for improved technique, care and cost is unlikely to be soon assuaged.
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