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Transplantability And Therapeutic Effects Of Bone Marrow-Derived Mesenchymal Cells In Children With Severe Osteogenesis Imperfecta.
Edwin M. Horwitz, Darwin J. Prockop, Lorraine A. Fitzpatrick, Winston, W.K. Koo, Patricia L. Gordon, Michael Neel, Michael Sussman, Paul Orchard, Jeffery C. Marx, Reed E. Pyeritz, Malcolm K. Brenner. St. Jude Children's Research Hospital, Memphis, MCP Hahnemann University, Philadelphia, Mayo Clinic, Rochester, Wayne State University, Detroit, Shriner's Hospital for Children, Portland, University of Minnesota, Minneapolis, Baylor College of Medicine, Houston. |
Bone marrow stromal cells are mesenchymal progenitor cells that have been shown to differentiate to bone and muscle in vitro and in vivo in murine model systems. In principle, transplantation of these marrow derived mesenchymal progenitor cells would attenuate or possible correct genetic disorders of bone, cartilage, and muscle, in humans, however, clinical data to support this concept is lacking. We will present data from our pilot study of allogeneic bone marrow transplantation as a means of transplanting marrow derived mesenchymal progenitor cells in children with severe osteogenesis imperfecta. Five children with osteogenesis imperfecta type III received a bone marrow transplant from an HLA compatible sibling. Each was given a conditioning regimen containing busulfan and cyclophosphamide prior to bone marrow transplant; in addition, one patient received moderate dose total body irradiation due to a mismatch at a single HLA DRB1 locus. All patients exhibited rapid hematopoietic recovery but three of five patients exhibited mixed chimerism. Ultimately, four of five patients developed full hematopoietic chimerism. Donor osteoblasts were documented by bone biopsy in three of four evaluable patients at 1.3-2.0%. Three months later, representative specimens of trabecular bone showed histologic changes indicative of dense bone formation. These findings were correlated with clinical data suggestive of improved osteogenesis. All patients showed an increase in total body bone mineral content at 100 days post transplant and a marked acceleration of growth velocity in the first 6 months post transplant as compared to the 6 months preceding transplant. A reduction in rate of fractures was noted in all patients with the most striking results for the two youngest and most severely affected patients. Three patients showed no significant toxicity. One child had transient pulmonary insufficiency and a bifrontal hygroma and one child developed stage 3 GVHD of the skin. All of these complications have resolved. Data obtained during 6-24 month follow-up of the children will be presented to illustrate our current concept of the natural history of patients with OI following mesenchymal cell transplantation. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of a mesenchymal cell strategy in the treatment of osteogenesis imperfecta. Future efforts will be directed towards reducing the risk of toxicity and enhancing mesenchymal engraftment predicting greater clinical benefit to the children. Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999. |