Systemic and local ex vivo gene therapy of the skeleton
Inventors
Baylink, David • Lau, Kin-Hing William • Chen, Wanqiu • ZHANG, XIAO-BING
Assignees
Loma Linda University • US Department of Veterans Affairs
Publication Number
US-9789162-B2
Publication Date
2017-10-17
Expiration Date
2035-11-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Methods are disclosed herein for increasing bone mass and strength or bone fracture healing in a subject. The methods include administering to the subject a therapeutically effective amount of multipotent stem cells, wherein each multipotent stem cell is transformed with a recombinant nucleic acid molecule comprising a heterologous promoter operably linked to a nucleic acid encoding platelet derived growth factor (PDGF) B, and wherein the multipotent stem cells express a sufficient amount of PDGFB to increase bone mass and strength or bone fracture healing. A lentiviral vector also is disclosed that includes a phosphoglycerate kinase-1 (PGK) promoter operably linked to a nucleic acid encoding PDGFB.
Core Innovation
The invention provides methods for increasing bone mass and strength or enhancing bone fracture healing in a subject by administering multipotent stem cells that are transformed with a recombinant nucleic acid molecule comprising a heterologous promoter operably linked to a nucleic acid encoding platelet derived growth factor (PDGF)B. Specifically, each multipotent stem cell expresses sufficient PDGFB to achieve the desired increase in bone mass, bone strength, or bone fracture healing. In particular embodiments, the invention discloses using a moderate promoter, such as the phosphoglycerate kinase-1 (PGK) promoter, to achieve targeted and sustained PDGFB expression in these cells.
The background discusses the limitations of current osteoporosis and bone defect treatments, noting that while existing antiresorptive and anabolic agents reduce fracture risk, they do not fully restore bone density or eliminate fracture risk and can have significant side effects. Therefore, there remains a need for therapies that can rejuvenate the osteoporotic skeleton to normal density and integrity, while minimizing adverse effects.
The solution described in the invention focuses on using transformed hematopoietic or mesenchymal stem cells that, when administered to a subject, localize to bone marrow niches and release PDGFB at levels sufficient for therapeutic effects. Notably, moderate expression levels, controlled by specific promoters such as PGK, lead to improved bone formation and strength without undesired side effects like osteomalacia. The method allows both systemic and local delivery of the stem cells, and includes embodiments where preconditioning (such as irradiation or myeloablation) is performed to facilitate engraftment.
Claims Coverage
The patent contains one independent claim, which is reflected in several main inventive features.
Method of increasing bone mass and strength using PDGFB-expressing hematopoietic stem cells
A method is provided that includes administering to a subject a therapeutically effective amount of hematopoietic stem cells transformed with a recombinant nucleic acid molecule encoding platelet derived growth factor (PDGF)B, operably linked to a phosphoglycerate kinase-1 (PGK) promoter. The transformed hematopoietic stem cells express PDGFB within the vascular niches in the marrow cavity, thereby increasing bone mass and strength in the subject.
The claim coverage centers on the administration of genetically modified hematopoietic stem cells with a PGK promoter-driven PDGFB expression to increase bone mass and strength, specifically detailing the method steps and biological context.
Stated Advantages
The methods avoid the formation of bones with low bone mineral density and resolve adverse effects such as osteomalacia seen with high PDGFB or FGF2 expression.
Moderate overexpression of PDGFB increases bone formation, bone strength, trabecular connections, and decreases cortical porosity.
The approach enables robust and functional new bone formation, leading to significant increases in bone mechanical strength.
The strategy can rejuvenate osteoporotic skeleton and completely replace bone lost in the osteoporotic process.
The therapy induces bone formation without affecting calcium, phosphate, or parathyroid hormone (PTH) homeostasis in the subject.
Documented Applications
Treatment for subjects undergoing bone marrow transplantation, including those preconditioned by total body irradiation.
Therapy for subjects with osteoporosis and other bone diseases or defects, such as fractures and metabolic bone diseases.
Enhancement of bone fracture healing in a subject.
Use in subjects with bone defects resulting from disease, injury, surgery, infection, malignancy, or developmental malformations.
Use to promote spinal fusion.
Treatment of transplantation-induced osteoporosis and bone loss.
Therapeutic application in genetic diseases resulting in abnormal bone formation, such as osteogenesis imperfecta or McCune-Albright syndrome.
Use in subjects with bone malignancies such as sarcoma or osteosarcoma.
Treatment for subjects having undergone total or partial body irradiation therapy resulting in bone fragility.
Interested in licensing this patent?