Horwitz (2002) - Isolated allogeneic bone marrow-derived...

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Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone Edwin M. Horwitz* , Patricia L. Gordon*, Winston K. K. Koo , Jeffrey C. Marx*, Michael D. Neel*, Rene Y. McNall*, Linda Muul § , and Ted Hofmann* *Transplantation and Gene Therapy Program, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105; Wayne State University, 4707 St. Antoine Boulevard, Detroit, MI 48201; and § Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 Communicated by Darwin J. Prockop, Tulane University, New Orleans, LA, April 26, 2002 (received for review April 18, 2002) Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affect- ing mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplan- tation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the ±rst 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex- matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically signi±cant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect en- graftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors. M arrow stromal cells (MSCs) are bone marrow-derived mesenchymal progenitors that can serve as long-term precursors for the regeneration of a variety of nonhematopoietic tissues, including bone, cartilage, muscle, and possibly neural elements (1–8). Preclinical studies have suggested that unma- nipulated bone marrow contains mixtures of mesenchymal pro- genitors, some possessing an unrestricted potential for mesen- chymal differentiation with others showing commitment to one or perhaps two lineages (9–14). This observation, together with recent advances in the isolation, expansion, and characterization of human MSCs, has raised the possibility of improved cell-based therapy for genetic disorders of mesenchymal tissues. However,
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This note was uploaded on 02/14/2011 for the course ORGANIC CH 341 taught by Professor Idk during the Spring '11 term at Wisconsin.

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Horwitz (2002) - Isolated allogeneic bone marrow-derived...

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