In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta

Abstract

Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (

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

“…44,45 The availability of Brtl mice will allow us to test such an approach for siRNA delivery by transducing Brtl mesenchymal stem cells with the lentiviral vector expressing the effective F-shRNA and transplanting them back to Brtl, as previously described. 20 Other novel tools may allow us to more safely manipulate mammalian cells than the use of lentivirus vectors. The identification in both human and mouse cells of specific and 'safe' loci for exogenous DNA integration, the AAVS1 and Rosa26, respectively, is particularly appealing.…”

“…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.…”

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

“…In humans, whole bone marrow and bone marrow mesenchymal stem cells (MSC) have been transplanted in OI children with gains in body length and bone mineralization [8,9], while allogeneic fetal liver-derived stem cells transplanted in utero led to apparent phenotypic improvement in an OI fetus, although confounded by concomitant bisphosphonate use [10]. In rodent OI models, transplantation of whole bone marrow/bone marrow MSC led to increased collagen content [11], improved bone strength, reduced perinatal lethality [12], and increased osteoblast differentiation [13,14]. Marked therapeutic benefits were shown following transplantation of fetal MSC from human first trimester blood in a mouse model of human type III OI (oim) including improved bone plasticity and a two-third reduction in long bone fractures [15,16].…”

Allele dependent silencing of collagen type I using small interfering RNAs targeting 3′UTR indels—A novel therapeutic approach in osteogenesis imperfecta

“…Studies of mosaic carriers of OI-causing mutations [31,32] and bone marrow transplantation experiments in patients with OI and murine OI-models have shown that even a very small increase in cells producing normal collagen can have a striking effect on bone phenotype [27,33,34]. This clearly supports that the relative increase in normal collagen described above could have dramatic effects on bone health.…”

“…There are also concerns of high cumulative doses of bisphosphonates in patients treated from infancy. There are small-scale studies and case reports on stem cell transplantation, bone marrow transplantation and gene therapy in patients with OI and in mouse models with varying results [26][27][28][29][30] but to date no clinically available therapy has developed out of these publications. This study was aimed at investigating a novel genetic therapeutic approach for treating or limiting the severity of this disease.…”