Enhancement of bone morphogenic protein (BMP) retention with BMP binding peptide (BBP)
Inventors
Murray, Samuel S. • Murray, Elsa • Wang, Jeffrey • Behnam, Keyvan
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-9072709-B2
Publication Date
2015-07-07
Expiration Date
2030-06-23
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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 comorbidities, 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 the binding and retention of bone morphogenic proteins (BMPs) and other growth factors of the TGF-β superfamily by growth factors including BMP Binding Peptide (BBP). This binding results in prolonged exposure of BMPs at the desired site of action, leading to earlier and increased mesodermal stem cell proliferation, chondrogenesis, osteogenesis, and calcification at sites such as fusion or repair sites.
The problem being addressed is the limitations of autogenous bone grafting, the current gold standard in bone graft surgeries. Although autogenous grafts are effective, they are associated with increased operative time, blood loss, donor-site morbidity, and limited availability especially in revision cases, multilevel constructs, or patients with medical comorbidities. Alternatives such as recombinant BMPs can overcome some of these issues but are limited by cost and side effects including inflammatory reactions, ectopic bone formation, and potential carcinogenicity in a dose-dependent manner.
The invention provides compositions and methods using BBP to bind and retain BMPs and related growth factors at the site of action, enhancing the rate and degree of osteogenesis and calcification. BBP acts synergistically with BMPs to reduce the amount of growth factor needed, thus improving clinical outcomes, reducing side effects, and decreasing treatment costs. Additionally, implants or compositions can be formed with BBP to maintain local concentrations of growth factors and improve bone repair or fusion.
Claims Coverage
The claims disclose three inventive features related to an article of manufacture incorporating BBP peptides and growth factors.
Article of manufacture comprising BBP peptide and growth factor to enhance osteogenesis
An article comprising a peptide with the amino acid sequence of SEQ ID NO: 11, or a fragment thereof, combined with at least one growth factor, wherein the peptide maintains a greater amount of growth factor in proximity to the article than growth factor alone, enhancing the degree or rate of osteogenesis in vertebrate cells.
Peptide with dissociation constant sufficient for growth factor retention
An article comprising the peptide of SEQ ID NO: 11, or a fragment, and at least one growth factor, where the peptide has a dissociation constant with the growth factor sufficient to retain more growth factor locally compared to growth factor alone, thereby enhancing osteogenesis in vertebrate cells.
Peptide with equilibrium constant enabling growth factor retention
An article comprising BBP peptide and at least one growth factor, where the peptide has an equilibrium constant with the growth factor sufficient to retain a greater amount of growth factor at the site compared to growth factor alone, enhancing the degree or rate of osteogenesis in vertebrate cells.
The claims cover articles of manufacture comprising a BBP peptide or fragment thereof combined with growth factors, where the peptides function to retain and maintain higher local concentrations of growth factors through specific binding characterized by dissociation or equilibrium constants, leading to enhanced osteogenesis in vertebrate cells.
Stated Advantages
BBP enhances the rate and/or degree of activity of selected growth factors such as BMPs.
BBP acts synergistically with TGF-β family members allowing effective outcomes at lower growth factor doses.
Combination of BBP with growth factors reduces treatment costs and unwanted side effects.
Sustained local concentration of BMP can be maintained, minimizing systemic or local side effects.
Documented Applications
Use in bone formation and repair including treatment of osteoporosis.
Bone injury treatment such as fracture healing of flat and long bones including non-union fractures and reconstructive surgery.
Sites of knee, hip, and joint repair or replacement surgery.
Periodontitis treatment, periodontal regeneration, and alveolar ridge augmentation for tooth implant reconstruction.
Incorporation into implants such as pins, screws, plates, or prosthetic joints to enhance bone stabilization and fusion.
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