(Verbatim from the Applicant): Regional gene therapy is a novel approach to enhance bone repair in humans. There is concern that a single exposure to exogenous recombinant protein may not induce a satisfactory osteoinductive stimulus in patients with significant bone loss. In previous work, we have demonstrated the efficacy of an ex vivo gene transfer strategy using BMP-2-producing rat bone marrow cells created via adenoviral gene transfer. These cells were used to heal a critical-sized femoral defect in rats. Our goal now is to further explore the potential of regional gene therapy so we can better adapt this technology for humans. The plan is to enhance our understanding of the biology of the bone repair process with ex vivo gene transfer by assessing the duration of BMP production in vivo and localizing the BMP secretion in the defect site over time. In addition, the role of the transduced bone marrow cells and host cells in the bone repair process will be determined, evaluating both the immune response to gene therapy and the presence of adenovirus at various anatomic sites. The research proposed in Specific Aim 1 will evaluate another cell type (skin fibroblasts) as a potential cellular delivery vehicle to heal critical-sized bone defects. The research proposed in Specific Aim 2 will investigate the efficacy of the ex vivo adenoviral gene transfer in a more stringent and clinically relevant model by trying to heal femoral defects in adult (12 month old) and elderly (18 month old) rats. In both Specific Aims 1 and 2, the duration of BMP production in vivo and the localization of BMP in the defect will be assessed.
In Specific Aim 3, the role of the BMP-2-producing bone marrow cells in the bone repair process and the donor cells will be assessed in a mouse model.
In Specific Aim 4, we will: (a) compare the efficacy of the ex vivo gene transfer strategy with BMP-2-producing bone marrow cells and direct in vivo injection of the virus; and (b) compare the safety and toxicity of these two gene therapy strategies. This proposed research will enhance our knowledge with respect to the potential pitfalls of gene therapy in enhancing bone repair and hopefully take us a step closer to adapting this technology for use in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046789-02
Application #
6497422
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Panagis, James S
Project Start
2001-04-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$326,414
Indirect Cost
Name
University of California Los Angeles
Department
Orthopedics
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Gamradt, Seth C; Abe, Nobuhiro; Bahamonde, Matthew E et al. (2006) Tracking expression of virally mediated BMP-2 in gene therapy for bone repair. Clin Orthop Relat Res 450:238-45
Feeley, Brian T; Conduah, Augustine H; Sugiyama, Osamu et al. (2006) In vivo molecular imaging of adenoviral versus lentiviral gene therapy in two bone formation models. J Orthop Res 24:1709-21
Feeley, Brian T; Liu, Nancy Q; Conduah, Augustine H et al. (2006) Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. J Bone Miner Res 21:1571-80
Vogelin, E; Jones, N F; Huang, J I et al. (2005) Healing of a critical-sized defect in the rat femur with use of a vascularized periosteal flap, a biodegradable matrix, and bone morphogenetic protein. J Bone Joint Surg Am 87:1323-31
Whang, Peter G; Schwarz, Edward M; Gamradt, Seth C et al. (2005) The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone. J Orthop Res 23:1475-83
Dragoo, Jason L; Lieberman, Jay R; Lee, Richard S et al. (2005) Tissue-engineered bone from BMP-2-transduced stem cells derived from human fat. Plast Reconstr Surg 115:1665-73
Peterson, Brett; Zhang, Jeffrey; Iglesias, Roberto et al. (2005) Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng 11:120-9
Sugiyama, Osamu; An, Dong Sung; Kung, Sam P K et al. (2005) Lentivirus-mediated gene transfer induces long-term transgene expression of BMP-2 in vitro and new bone formation in vivo. Mol Ther 11:390-8
Peterson, Brett; Iglesias, Roberto; Zhang, Jeffrey et al. (2005) Genetically modified human derived bone marrow cells for posterolateral lumbar spine fusion in athymic rats: beyond conventional autologous bone grafting. Spine (Phila Pa 1976) 30:283-9; discussion 289-90

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