Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta

Abstract

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

Restoration of cellular function of mesenchymal stem cells from a hypophosphatasia patient

“…Therefore, bone marrow transplantation has been undertaken in patients with genetic bone diseases, for example osteogenesis imperfecta and may have a therapeutic effect in osteogenesis imperfecta. 21,22 In hypophosphatasia, allogeneic bone marrow and/or MSC transplantation therapy has been reported by us and other groups. 4,14,23 However, the disease was not curable with these allo-transplantation therapies.…”

Adult bone marrow–derived stem cells for organ regeneration and repair

“…The safety of autologous and allogeneic MSC products has been established in these trials and no toxicity was documented. Due to the ability of MSCs to differentiate into osteocytes, they have been used as adjunct therapy to marrow transplantation in osteogenesis imperfecta (Horwitz et al, 1999(Horwitz et al, , 2002. The rationale was to introduce cells with a healthy gene that produce physiologic bone matrix.…”

Gene therapy approaches for osteogenesis imperfecta

“…Three of the children who received bone marrow transplantation were documented to exhibit donor osteoblasts in their bones 3 months after cell transplantation. 44 The children who were shown to possess osteoblast engraftment after 6 months of marrow infusion were reported to exhibit an increase in body length. The patients also gained 45-77% of total bone mineral content from the baseline values and also exhibited a reduction in fracture rates.…”

“…The authors concluded that bone marrow transplantation from normal donors to OI patients might be of benefit in OI. [44][45][46] The number of donor cells that engrafted in marrow recipients was however very small. At 3 months after bone marrow transplantation, only 1.5-2% of the cells in trabecular bone of the cell recipients were estimated to be of the donor origin.…”