Hematopoietic stem cell–targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice

Johansson, Madeleine; Vries, Teun J. de; Schoenmaker, Ton; Ehinger, Mats; Brun, Ann; Fasth, Anders; Karlsson, Stefán; Everts, Vincent; Richter, Johan

doi:10.1182/blood-2006-12-061382

Cited by 41 publications

(36 citation statements)

References 32 publications

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“…(9,10) Previously, it has been shown that the severe oc/oc mouse model of IMO, which also has a deletion in the Tcirg1 gene, can be rescued by transplantation in utero (11,12) or by neonatal transplantation of normal bone marrow (BM) or genetically modified oc/oc fetal liver cells after conditioning with irradiation or busulfan. (13)(14)(15) In this study we aimed to determine if neonatal transplantation without any prior conditioning could reverse osteopetrosis and rescue oc/oc mice and in detail study the prerequisite and characteristics of this process. The objectives for this study were not only to further advance the development of cell and gene therapy of this disease but also to gain more insight into the role and capacity of osteoclasts in remodeling of bone tissue in vivo.…”

Section: J Jbmrmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

“…(14,15) Litters were genotyped by PCR of tail tips, as described previously. (15) Both wild-type (WT) and oc/þ mice, which are phenotypically indistinguishable from WT littermates, were used as recipient controls. Bl6SJL (Ly5.1) or transgenic GFP þ mice (16) were used as bone marrow donors in transplantation experiments, which were performed via intravenous injection using the temporal vein.…”

Section: Micementioning

confidence: 99%

“…(14,15) In addition, splenocytes were isolated from harvested minced spleens by passing through a 100-mm filter. Antibodies directed against Ly5.1-PE and Ly5.2-FITC were used for engraftment analysis and B220-APC, CD3-PE, Gr1-APC, and CD11b-PE (Pharmingen, Becton Dickinson) were used for lineage analysis using a fluorescence-activated cell sorting (FACS) Calibur Instrument or FACS CantoII (Becton Dickinson).…”

Section: Micementioning

confidence: 99%

“…Real-time PCR was performed on a LightCycler (Roche Diagnostics, Mannheim, Germany) using standard conditions with cDNA equivalent to 10 ng of RNA and 1:20000 dilution of SybrGreen I. (15) The following primers were used: rankl, forward: 5 0 -CCAAGATCTC-TAACATGACG-3 0 ; reverse: 5 0 -CACCATCAGCTGAAGATAGT-3 0 ; actin, forward: 5 0 -CACCACAGCTGAGAGGGAAA -3 0 ; reverse: 5 0 -GTCAGGCAGCTCATAGCTCTT-3 0 ; m-csf, forward: 5 0 -TTAAAGA-CAACACCCCCAATGC-3 0 ; reverse: 5 0 -TCAGGTTATTGGAGAGTTC-CTGGA-3 0 . Differences in gene expression were calculated using the 2 -DDCt method.…”

Section: Micro-computed Tomographic (Mct) Imagingmentioning

confidence: 99%

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Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Flores

Vries

Moscatelli

et al. 2010

Journal of Bone and Mineral Research

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Infantile malignant osteopetrosis (IMO) is caused by lack of functional osteoclasts leading to skeletal abnormalities, blindness owing to compression of the optic nerves, bone marrow (BM) failure, and early death. In most patients, TCIRG1, a proton pump subunit essential for bone resorption, is mutated. oc/oc mice represent a model for IMO owing to a deletion in Tcirg1 and die around 4 weeks of age. To determine if hematopoietic stem cell transplantation without prior conditioning can reverse osteopetrosis, neonatal mice were transplanted intravenously with lineage-depleted BM cells. More than 85% of oc/oc mice transplanted with 5 Â 10 6 cells survived long term with an engraftment of 3% to 5% in peripheral blood (PB). At 3 weeks, engraftment in the BM was 1% to 2%, but the cellularity had increased 60-fold compared with untreated oc/oc mice, and RANKL and macrophage colony-stimulating factor (M-CSF) expression in the BM was normalized. Histopathology and micro-computed tomography revealed almost complete reversal of osteopetrosis after 4 weeks. In vitro studies showed that bone resorption by osteoclasts from transplanted oc/oc mice was 14% of transplanted controls, and immunofluorescence microscopy revealed that resorption was mainly associated with osteoclasts of donor origin. Lineage analysis of BM, PB, and spleen did not provide any evidence for selective recruitment of cells to the osteoclastic lineage. The vision also was preserved in transplanted oc/oc mice, as determined by a visual tracking drum test. In summary, nonablative neonatal transplantation leading to engraftment of only a small fraction of normal cells rapidly reverses severe osteopetrosis in the oc/oc mouse model. ß

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Section: J Jbmrmentioning

confidence: 99%

Section: Micementioning

confidence: 99%

Section: Micementioning

confidence: 99%

Section: Micementioning

confidence: 99%

Section: Micro-computed Tomographic (Mct) Imagingmentioning

confidence: 99%

See 3 more Smart Citations

Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Flores

Vries

Moscatelli

et al. 2010

Journal of Bone and Mineral Research

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A single‐center experience in 20 patients with infantile malignant osteopetrosis

et al. 2009

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Infantile malignant osteopetrosis (IMO) includes various genetic disorders that affect osteoclast development and/or function. Genotype-phenotype correlation studies in IMO have been hampered by the rarity and heterogeneity of the disease and by the severity of the clinical course, which often leads to death early in life. We report on the clinical and molecular findings and treatment in 20 consecutive patients (11 males, nine females) with IMO, diagnosed at a single center in the period 1991-2008. Mean age at diagnosis was 3.9 months, and mean follow-up was 66.75 months. Mutations in TCIRG1, OSTM1, ClCN7, and TNFRSF11A genes were detected in nine, three, one, and one patients, respectively. Six patients remain genetically undefined. OSTM1 and ClCN7 mutations were associated with poor neurologic outcome. Among nine patients with TCIRG1 defects, six presented with hypogammaglobulinemia, and one showed primary pulmonary hypertension. Fourteen patients received hematopoietic cell transplantation; of these, nine are alive and eight of them have evidence of osteoclast function. These data may provide a basis for informed decisions regarding the care of patients with IMO. Am. J. Hematol. 84:473-479, 2009. V

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Osteopetrosis—More than only a disease of the bone

Fasth

2009

American J Hematol

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Hematopoietic stem cell–targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice

Cited by 41 publications

References 32 publications

Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

A single‐center experience in 20 patients with infantile malignant osteopetrosis

Osteopetrosis—More than only a disease of the bone

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