Compositions and methods relating to bone repair and regeneration
Inventors
Assignees
Publication Number
US-12036265-B2
Publication Date
2024-07-16
Expiration Date
2041-06-29
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Abstract
Methods of treating a subject in need thereof are provided which include: administering a recombinant platelet derived growth factor D (PDGF D) composition to a mesenchymal stem cell of the subject and/or a progenitor derived therefrom, in vivo, or ex vivo, producing a treated mesenchymal stem cell of the subject and/or a progenitor derived therefrom, thereby stimulating the mesenchymal stem cell (MSC) and/or a progenitor derived therefrom. Cells expressing a recombinant PDGF D composition of the present are administered to the subject for in vivo delivery of the recombinant PDGF D composition according to aspects of the present disclosure. Methods and compositions are provided including recombinant PDGF D hemidimer (HD) including a full-length PDGF D polypeptide and a C-terminal growth factor domain of PDGF D, which lacks a CUB domain, promoting regulation of bone marrow MSC differentiation into osteogenic lineage cells.
Core Innovation
The invention provides methods and compositions for stimulating bone repair and regeneration by administering recombinant platelet-derived growth factor D (PDGF D) compositions—specifically, a hemidimer (HD) comprising a full-length PDGF D polypeptide and a C-terminal growth factor domain (GFD) of PDGF D that notably lacks a CUB domain. These compositions can be administered to mesenchymal stem cells (MSCs) or progenitors thereof, in vivo or ex vivo, leading to the stimulation of those stem cells and their differentiation into osteogenic lineage cells. Administration can be via recombinant proteins or nucleic acids encoding the relevant polypeptides, and treated cells may be delivered back into the subject.
The background outlines that while bone formation is influenced by several growth factors, such as TGF-β and BMPs, administration of these factors alone has shown limited effectiveness and often requires supraphysiological concentrations. PDGF B and D activate β-PDGFR; however, PDGF D exhibits unique regulatory functions in bone marrow mesenchymal stem cell differentiation not shared by PDGF B. The present invention responds to a continuing need for more effective compositions and methods to promote bone repair and regeneration.
The core of this innovation lies in the tailored use of specific PDGF D dimeric forms—particularly the hemidimer and/or the GFD dimer—to direct mesenchymal stem cell fate. The PDGF D HD stimulates early differentiation of MSCs into osteoprogenitors through β-PDGFR/TGFβR/SMAD signaling, while the GFD dimer promotes maturation into osteoblasts and inhibits adipocyte differentiation. The invention also contemplates the use of edible, protease-resistant, or mutated forms for enhanced stability, as well as methods of delivery using expression vectors, pharmaceutical compositions, and implants.
Claims Coverage
There are three main independent claim groups in the patent, each defining a distinctive inventive feature regarding compositions and methods for stimulating bone growth or inhibiting adipocyte differentiation involving recombinant PDGF D constructs.
Pharmaceutical composition comprising isolated recombinant PDGF D hemidimer and GFD dimer
A pharmaceutical composition that includes: - An isolated recombinant platelet-derived growth factor D (PDGF D) wild-type hemidimer (HD) or isolated recombinant cleavage-resistant hemidimer (CR-HD). - An isolated recombinant growth factor domain (GFD) dimer. - A pharmaceutically acceptable carrier. - The PDGF D hemidimer and GFD dimer are provided as separate moieties.
Composition comprising nucleic acids encoding PDGF D full length and GFD subunit
A composition that includes: - A nucleic acid encoding the PDGF D full-length subunit polypeptide found in the hemidimer. - A nucleic acid encoding the GFD subunit polypeptide found in the GFD dimer.
Method of treating a subject by administering recombinant PDGF D hemidimer and GFD dimer compositions to mesenchymal stem cells
A method of treating a subject in need thereof comprising: - Administering a recombinant PDGF D composition to a mesenchymal stem cell and/or a progenitor derived therefrom. - Producing a treated mesenchymal stem cell and/or progenitor. - The PDGF D composition consists of an isolated recombinant platelet-derived growth factor D (PDGF D) wild-type hemidimer or isolated recombinant cleavage-resistant hemidimer (CR-HD) and an isolated recombinant growth factor domain (GFD) dimer, provided as separate moieties. - The treated cells stimulate bone growth or inhibit adipocyte formation.
The inventive features broadly cover compositions and methods utilizing recombinant PDGF D hemidimer and GFD dimer—whether as proteins or encoded by nucleic acids—for stimulating bone growth or inhibiting adipocytes, including detailed requirements for their structure, administration, and pharmaceutical formulation.
Stated Advantages
PDGF D hemidimer compositions stimulate differentiation of mesenchymal stem cells into osteogenic lineage cells, promoting bone repair and regeneration.
The use of PDGF D GFD dimer inhibits adipocyte differentiation in mesenchymal stem cells, which is beneficial for conditions involving age-associated bone loss with increased adipogenesis.
The described methods and compositions provide enhanced bone regeneration compared to conventional growth factors (such as BMPs or TGF-β) that require higher concentrations and demonstrate limited clinical efficacy.
PDGF D compositions can be used in both in vivo and ex vivo protocols, offering flexibility in clinical applications.
Documented Applications
Treating subjects in need of bone repair or bone regeneration, including those with bone injury, bone loss due to trauma, surgery, aging, disease, bone fracture, osteoporosis, dental procedures, surgical procedures, cancer, and metabolic disorders such as hyperparathyroidism.
Inhibiting adipocyte differentiation in subjects with age-associated bone loss and increased adipogenesis, as well as other metabolic disorders including diabetes and obesity.
Use in drug delivery implants, including orthopedic implant devices incorporating the PDGF D hemidimer and GFD dimer, for localized stimulation of bone growth and regeneration.
Production of transgenic non-human animals (such as mice) expressing PDGF D hemidimer and/or GFD dimer proteins for studying bone disorders and treatments.
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