Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta

Abstract

Preclinical models have shown that transplantation of marrow mesenchymal cells has the potential to correct inherited disorders of bone, cartilage, and muscle. The report describes clinical responses of the first children to undergo allogeneic bone marrow transplantation (BMT) for severe osteogenesis imperfecta (OI), a genetic disorder characterized by defective type I collagen, osteopenia, bone fragility, severe bony deformities, and growth retardation. Five children with severe OI were enrolled in a study of BMT from human leukocyte antigen (HLA)-compatible sibling donors. Linear growth, bone mineralization, and fracture rate were taken as measures of treatment response. The 3 children with documented donor osteoblast engraftment had a median 7.5-cm increase in body length (range, 6.5-8.0 cm) 6 months after transplantation compared with 1.25 cm (range, 1.0-1.5 cm) for age-matched control patients. These patients gained 21.0 to 65.3 g total body bone mineral content by 3 months after treatment or 45% to 77% of their baseline values. With extended follow-up, the patients' growth rates either slowed or reached a plateau phase. Bone mineral content continued to increase at a rate similar to that for weight-matched healthy children, even as growth rates declined. These results suggest that BMT from HLA-compatible donors may benefit children with severe OI. IntroductionBone marrow mesenchymal cells can differentiate to a variety of tissues including bone, cartilage, muscle, and fat. 1-7 Thus, in principle, bone marrow transplantation (BMT) could provide effective therapy for disorders that involve cells derived from mesenchymal precursors. 8 One attractive candidate is osteogenesis imperfecta (OI) or "brittle bone disease," a genetic disorder caused by defects in type I collagen, the major structural protein of the extracellular matrix of bone. [9][10][11] Patients with severe OI have numerous painful fractures, progressive deformities of the limbs and spine, retarded bone growth, and short stature. There is no cure for OI, and only one class of drugs, the bisphosphonates, which can reduce or prevent bone resorption, appear to have therapeutic potential. [12][13][14] Ideally, therapy for OI should be directed toward improving bone strength by improving the structural integrity of collagen and thereby the quality of the bone. 15,16 Although the existence of circulating osteoblast progenitors is controversial, 17 preclinical studies have demonstrated that whole bone marrow contains cells that can engraft and become competent osteoblasts after transplantation. 18 Moreover, because collagen is a secreted product, even a low level of osteoblast engraftment might be beneficial to OI patients. 6,19 Guided by this rationale, we undertook a pilot study to demonstrate the feasibility of transplanting bone marrow-derived mesenchymal cells in children with OI.Although providing a basis for continued testing of this strategy, our initial analysis 20 included only 6 months of clinical follow-up and did not directly compare resul...

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells

“…Several phase I-II clinical trials have already shown the safety and efficacy of BM-derived MSCs for enhancing the engraftment of co-transplanted HSCs in patients with hematologic and non-hematologic malignancies [37,38]. BM-derived MSCs have also shown promising results for the treatment of mesenchymal diseases such as osteogenesis imperfecta [39] and congenital disorders such as metachromatic leukodystrophy [40]. BM-derived MSCs have shown to be safe in phase-I trials in myocardial infarction patients [41].…”

Bone Material Properties in Osteogenesis Imperfecta

“…Murine (oim-/-) studies suggest that mesenchymal stem cells (MSCs) can engraft and produce normal collagen ameliorating the OI phenotype and reducing bone brittleness, (102)(103)(104) and human chorionic cells transplanted into newborn oim-/-mice also improved the clinical phenotype. (105) Previous human studies of bone marrow transplantation showed little mesenchymal lineage engraftment and failed to deliver clear benefit, (106,107) but the recent report of fetal stem cell infusion both before and after delivery in a child thought to have type IV OI was encouraging. (108) Ex vivo manipulation of cells and then their reintroduction has been widely discussed after the recent successful treatment of a child with leukemia.…”

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

“…Thus, for clinically significant OI caused by structural defects in collagen, suppression of the Mut allele could in principle convert severe types III and IV to the minimally symptomatic OI type I, a situation particularly favorable to therapeutic strategies based on gene silencing. The promising preliminary data on stem cell transplantation in both murine models [18][19][20] and human OI 21,22 contributes to an appealing possibility for correcting the patient's own stem cells in vitro, and transplanting them back to the patient, after checking chromosomal rearrangements 23 or off-target effects 24 in vitro.…”