Novel Formulations for Injectable Growth Factors

DESCRIPTION (provided by applicant): Over 6.3 million fractures occur each year in the United States alone (Praemer et al. 1999) and approximately 15% of fractures exhibit delayed or impaired healing. The clinical applications currently used to treat delayed fracture require open surgery to insert an autologous bone graft. If open surgery is confounded by co-morbidity or is deemed otherwise undesirable, a minimally invasive injectable therapy would provide patients and physicians with another treatment option. Growth factors, particularly bone morphogenetic proteins (BMPs) are employed for a range of indications including spinal fusion and fracture healing due to their potent osteogenic activity (Mont et al. 2004). An injectable BMP carrier would provide a carrier for the minimally invasive application of this powerful family of therapeutic molecules. (*1) During the Phase I funding period, we explored a novel approach toward developing an injectable delivery system for BMPs, specifically FDA-approved BMP-2. We generated two formulations for this potential product: a collagen matrix on which BMP-2 binding peptides were covalently attached and a second where a collagen matrix was mixed with a bifunctional peptide, comprised of a binding domain with high-affinity for collagen and another domain with high-affinity for BMP-2. The first formulation fulfilled our in vitro efficacy criteria, but failed to form a stable hydrogel leading to its failure in our in vivo osteoinduction model. The second formulation, containing bifunctional BMP-2: collagen peptides appeared to satisfy both our in vitro and in vivo performance criteria. The technology developed in Phase 1, and proposed here for commercial optimization in Phase 2, represents a unique biomaterial, potentially useful for a number of medical indications. Our Phase 2 proposal has 3 discrete aims: 1) optimize peptide sequence and synthesis for commercial scale production and formulation; 2) examine the biocompatibility, toxicity and stability of each modified hydrogel and 3) test the in vivo osteogenic efficacy of our injectable carriers in a rabbit osteotomy model. The development of a new delivery matrix, using peptide binders for BMP-2, may allow for a greater degree of controlled growth factor release. Specifically, an injectable BMP-2 formulation would allow for the treatment of fractures with a minimally invasive procedure. Broadly applied, injectable growth factors are likely to enhance the biological components of healing, encouraging simpler surgical intervention, faster healing and improved outcomes. By combining noninvasive injectability with a targeted, molecular therapy we hope to increase localized retention of biologics while decreasing their dosages, and concomitant expense. (*3) We feel this platform for BMP-2 delivery could be used as a model for other growth factors, such as PDGF-BB, TGF-3 or GDF7, for which Affinergy has already developed high-affinity binding peptides. Guiding our prototype BMP-2 delivery system toward commercialization represents our first step toward investigating the broad applications of injectable growth factors. PUBLIC HEALTH RELEVANCE: Growth factors called Bone Morphogenetic Proteins (BMPs) are currently used to promote osteogenesis and fracture healing. Over 6.3 million fractures occur each year in the United States alone and approximately 15% of fractures exhibit delayed or impaired healing. The clinical applications currently in use, however, require open surgery to insert the carrier/BMP combination at the site of healing. There would be considerable clinical benefit from the ability to deliver BMPs via a minimally invasive procedure. In this proposal, we present a novel approach to continue the development of an injectable delivery system for BMP-2 that improves the retention and effectiveness of a growth factor at the site of repair. Expanding this technology to other therapeutic proteins could generate novel interventions for additional medical indications.