Research Project
7611713
DESCRIPTION (provided by applicant): Of the nearly 5 million patients who visit a physician for tendon pain each year in the US, approximately 200,000 go on to have a surgical repair. And while surgical repair has a high-rate of symptom relief, recovering patients are routinely immobilized for several months. Increased tendon strength, during shorter time courses has been reported in animal models using the localized delivery of growth factors with surgical tendon repair. In particular, the growth and differentiation factors 5 and 7 (GDF5 and GDF7) are required for proper tendon formation, and have been shown to dramatically improve healing when applied to damaged tendon tissue. Here we propose the manufacture of a peptide-based coating, permitting the loading of these growth factors to the sutures used during surgical repair of tendon tissue to promote their sustained release. Using phage display technology, Affinergy has screened libraries expressing billions of peptide sequences, searching for those peptides which bind biologic therapeutics and synthetic materials. From previously identified peptides, several were identified which bind to suture materials, however GDF7/5 binding peptides were not immediately available from those already synthesized. Therefore a new round of phage display biopanning was performed with immobilized GDF7 as a target. For this round of phage display, a focused phage library was used, originally designed to find peptides specific for BMP-2, another TGF-[unreadable] superfamily member. This library revealed several peptide sequences capable of binding GDF7 with sub [unreadable]M affinity. After identifying these sequences, a conjugation strategy, attaching suture- and GDF7-binding peptides through a biotin:streptavidin system, was used to test their potential efficacy as a bifunctional linker molecule. These conjugates were capable of retaining bioactive GDF7 to a suture surface, as well as sustaining its release to surrounding cells. Finally, these peptides were synthesized as one continuous linear peptide, to generate a bifunctional peptide, which did not exhibit similar affinity compared to the streptavidin conjugate linkers. New IFBM formulations are therefore proposed, which replicate the peptide composition and orientation of the streptavidin conjugated molecules. Early optimization of IFBMs using new linkage chemistries and orientations have resulted in bifunctional peptides which enhance GDF7 attachment to suture surfaces. We are therefore eager to initiate additional optimization activities to further enhance these peptides. These data provide initial proof-of-concept evidence that bioactive GDF7 can be delivered on the surface of sutures through a novel GDF7:suture binding peptide. Exploring the in vivo function, and initiating product development is now essential to determine the therapeutic efficacy and commercial viability of this growth factor delivery platform. PUBLIC HEALTH RELEVANCE: With the most active senior generation in history rapidly emerging, the need for innovative therapeutics to treat problematic joints and tendons continues to grow. Here we present data from the successful completion of our Phase I research program, developing a peptide-based suture coating for the controlled delivery of growth and differentiation factors (GDFs) to surgically repaired tendons. The prototype coating developed in Phase I will be further optimized in Phase II, using new peptide conjugation and ligation chemistries devised by Affinergy. We will also further validate our peptide coatings in preparation for an in vivo animal model of surgical tendon repair. These animal studies will provide the first evidence for the efficacy and feasibility of our peptides for the localized delivery of GDF on suture after surgical repair.
