Enhancement of bone morphogenic protein (BMP) retention with BMP binding peptide (BBP)
Inventors
Murray, Samuel S. • Murray, Elsa J. • Wang, Jeffrey • Behnam, Keyvan
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-9694047-B2
Publication Date
2017-07-04
Expiration Date
2030-06-23
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The use of autogenous bone graft is the current gold standard in the 1.5 million bone-grafting surgeries performed annually in the United States. Although this practice has resulted in high rates of fusion success, it is associated with increased operative time and blood loss, along with a significant degree of donor-site morbidity. Additionally, in certain settings such as revision cases, multilevel constructs, or in patients with medical co-morbidities, autogenous bone graft may exist in limited quantity and quality. This significant need for a suitable alternative to autogenous bone graft has stimulated great interest in the exploration of bone graft substitutes and extenders.
Core Innovation
The invention relates to compositions and methods involving the bone morphogenic protein binding peptide (BBP) to bind and retain bone morphogenic proteins (BMPs), members of the transforming growth factor-beta (TGF-β) superfamily, and other growth factors at desired sites of action. This retention prolongs exposure of BMPs and related growth factors, leading to earlier and enhanced mesodermal stem cell proliferation, chondrogenesis, osteogenesis, and calcification, particularly at bone fusion or repair sites. BBP is a synthetic, cyclic 19 amino acid peptide derived from a fragment of a secreted phosphoprotein (SPP-24) and possesses a cystatin-like domain that binds BMPs such as BMP-2 and BMP-7.
The problem addressed by the invention is the limitations associated with the current gold standard in bone grafting surgeries: autogenous bone graft. Autogenous bone grafts, though effective, present challenges including increased operative time, blood loss, donor-site morbidity, and limited availability in certain clinical situations. While recombinant BMPs like rhBMP-2 and rhOP-1 offer alternatives, their use is constrained by high costs and dose-dependent adverse events such as local inflammation, ectopic bone formation, and theoretical cancer risks. There is a significant need for safe, effective, and affordable compositions and methods to enhance bone formation and repair that overcome these issues.
The invention solves this problem by applying BBP in combination with BMPs or other TGF-β family members to enhance osteogenesis and calcification through increased retention and concentration of these growth factors at the target site. BBP acts synergistically with BMPs, enabling faster and more extensive bone formation with lower doses of growth factors, potentially reducing side effects and costs. The invention also encompasses implants and compositions where BBP is used alone or with cells or other growth factors, thus broadening bone healing and repair applications.
Claims Coverage
The patent includes 14 method claims focusing on the application of BBP in combination with TGF-β family member growth factors to enhance bone formation and related biological processes.
Use of BBP with TGF-β family growth factors to enhance bone formation
Applying a combination of bone morphogenic protein binding peptide (BBP) having the amino acid sequence of SEQ ID NO:11, SEQ ID NO:1, or SEQ ID NO:13 with at least one transforming growth factor-beta (TGF-β) family member growth factor to a desired site to enhance the rate or degree of bone formation in a vertebrate.
Retention of growth factors by BBP at the site of application
The BBP maintains or retains an amount of the TGF-β family member growth factor at the site longer than the growth factor alone by having a dissociation constant or equilibrium constant sufficient for retention.
Selection of TGF-β family members
The TGF-β family member used with BBP is selected from BMP-2, BMP-4, BMP-7, TGF-β, or GDF-5.
Enhancement of related biological processes
Using BBP and TGF-β family member combinations to enhance mesodermal stem cell proliferation, chondrogenesis, osteogenesis, and calcification in bone by retaining growth factors longer at the tissue than with the growth factor alone.
The claims cover methods of applying BBP with specific TGF-β family members to prolong growth factor retention at bone repair sites, thereby enhancing bone formation and related biological activities effectively and efficiently.
Stated Advantages
BBP enhances the rate and degree of activity of BMPs and related growth factors, leading to faster and greater bone formation.
BBP acts synergistically with TGF-β family members, reducing the required dose of growth factors, which lowers associated treatment costs and adverse effects.
Use of BBP with BMPs improves clinical outcomes by achieving earlier and greater bone fusion or repair.
BBP increases retention and slow release of BMPs at the site of action, prolonging effective exposure to growth factors.
Documented Applications
Inducing bone formation or repair, including bone fusion.
Treatment of bone disorders such as osteoporosis.
Healing bone injuries including fractures, non-union fractures, and reconstructive surgery.
Support for orthopedic procedures including spinal fusion, site of knee/hip/joint repair or replacement surgery.
Periodontal applications such as treatment of periodontitis, periodontal regeneration, and alveolar ridge augmentation for tooth implant reconstruction.
Use in implants such as pins, screws, plates, and prosthetic joints coated or containing BBP and/or growth factors to enhance bone formation and stabilization.
Interested in licensing this patent?