Adeno-associated virus (AAV) vectors are ideal for the long-term treatment of metabolic defects. Unique features including non-pathogenicity, low-immunogenicity and stable expression have positively resulted in successful preclinical and clinical evaluation of this vector. One of the potential, yet, unexplored areas of gene therapy using rAAV is metabolic bone defects characterized by a reduction in the mass of bone per unit volume as in osteoporosis or insufficient mechanisms for anabolic bone remodeling as in spinal fusion and fracture. Although, currently available hormonal and drug therapies for osteopenia aim to prevent further bone destruction by osteoclasts, therapies directed towards increasing bone mass by increasing the event of osteogenesis will be greatly beneficial. Treatments to increase bone density by anabolic agents are limited due to ineffective delivery methods and a short half-life of the drugs and purified proteins. Thus, novel methods to induce sustained in vivo osteogenesis should improve the pathophysiology of the disease. Our earlier studies established long-term efficacy of rAAV-transduced mesenchymal stem cells (MSC) to selectively engraft to bone, repopulate and express a transgene in a mouse model. Preliminary studies pertaining to this application indicated that recombinant AAV-2 (rAAV) transduces human and murine MSC and osteoprogenitors in high-efficiency and that rAAV-mediated transfer of bone morphogenetic protein-2 (BMP-2) leads to their differentiation into osteoblast lineage. Thus, we hypothesize that autologous transplantation of culture-expanded MSC, transduced with rAAV encoding BMP-2 under the control of osteoprogenitor-specific promoters, will result in osteoblast enrichment and increased bone mass. In the current proposal, we will evaluate this hypothesis to: 1) Determine the engraftment of ex vivo cultured MSC and optimize enrichment of homing to bone by ectopic expression of a bone homing signal, 2) Determine bone-specific expression of BMP-2 and its osteogenic significance in vivo and 3) Determine the effects of AAV-mediated gene therapy in osteopenic mice models in vivo. A successful outcome of these studies may form the basis for future development of gene therapy approaches for osteoporosis and other osteopenic diseases in humans.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZRG1-GTIE (90))
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Sharrock, William J
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University of Alabama Birmingham
Schools of Medicine
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Higgs, Jerome T; Jarboe, John S; Lee, Joo Hyoung et al. (2015) Variants of Osteoprotegerin Lacking TRAIL Binding for Therapeutic Bone Remodeling in Osteolytic Malignancies. Mol Cancer Res 13:819-27
Sawant, Anandi; Deshane, Jessy; Jules, Joel et al. (2013) Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res 73:672-82
Sawant, Anandi; Ponnazhagan, Selvarangan (2013) Myeloid-derived suppressor cells as osteoclast progenitors: a novel target for controlling osteolytic bone metastasis. Cancer Res 73:4606-10
Sawant, Anandi; Hensel, Jonathan A; Chanda, Diptiman et al. (2012) Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J Immunol 189:4258-65
Sawant, Anandi; Chanda, Diptiman; Isayeva, Tatyana et al. (2012) Noggin is novel inducer of mesenchymal stem cell adipogenesis: implications for bone health and obesity. J Biol Chem 287:12241-9
Kumar, Sanjay; Ponnazhagan, Selvarangan (2012) Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect. Bone 50:1012-8
Kumar, S; Nagy, T R; Ponnazhagan, S (2010) Therapeutic potential of genetically modified adult stem cells for osteopenia. Gene Ther 17:105-16
Kumar, Sanjay; Wan, Chao; Ramaswamy, Girish et al. (2010) Mesenchymal stem cells expressing osteogenic and angiogenic factors synergistically enhance bone formation in a mouse model of segmental bone defect. Mol Ther 18:1026-34
Chanda, Diptiman; Kumar, Sanjay; Ponnazhagan, Selvarangan (2010) Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. J Cell Biochem 111:249-57
Chanda, Diptiman; Isayeva, Tatyana; Kumar, Sanjay et al. (2009) Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in prostate cancer bone metastasis. Clin Cancer Res 15:7175-85

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