(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.
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