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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5178-5185. Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2006-12-061382. This Article Full Text (PDF) All Versions of this Article: blood-2006-12-061382v1 109/12/5178    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johansson, M. K Articles by Richter, J. Search for Related Content PubMed PubMed Citation Articles by Johansson, M. K Articles by Richter, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 21, 2006 Accepted February 15, 2007 Hematopoietic stem cell targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice Maria K Johansson, Teun J de Vries, Ton Schoenmaker, Mats Ehinger, Ann CM Brun, Anders Fasth, Stefan Karlsson, Vincent Everts, and Johan Richter* Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden Department of Periodontology and Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), Universiteit van Amsterdam and Vrije Universiteit, Amsterdam, Netherlands Department of Pathology, Lund University, Lund, Sweden Department of Pediatrics, Goteborg University, Gothenburg, Sweden * Corresponding author; email: johan.richter{at}med.lu.se. Infantile malignant osteopetrosis (IMO) is a fatal disease caused by lack of functional osteoclasts and the only available treatment is hematopoietic stem cell (HSC) transplantation. In the majority of patients the TCIRG1 gene, coding for a subunit of a proton pump essential for bone resorption, is mutated. Oc/oc mice have a deletion in the homologue gene (tcigr1) and die at 3-4 weeks, but can be rescued by neonatal transplantation of HSCs. Here HSC targeted gene therapy of osteopetrosis in the oc/oc mouse model was developed. Oc/oc fetal liver cells depleted of Ter119-expressing erythroid cells were transduced with a retroviral vector expressing tcirg1 and GFP, and subsequently transplanted i.p. to irradiated neonatal oc/oc mice. 8/15 mice survived past the normal lifespan of oc/oc mice. In vitro osteoclastogenesis revealed formation of GFP positive osteoclasts and bone resorption, albeit at a lower level than from wild-type cells. The skeletal phenotype was analyzed by X-ray and histopathology and showed partial correction at 8 weeks and almost normalization after 18 weeks. In summary, osteopetrosis in oc/oc mice can be reversed by neonatal transplantation of gene modified HSCs leading to long-term survival. This represents a significant step towards the development of gene therapy for osteopetrosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Gene therapy sculpts the bone Luigi D. Notarangelo Blood 2007 109: 5067-5068. [Full Text] [PDF] This article has been cited by other articles: E. M. van Beek, T. J. de Vries, L. Mulder, T. Schoenmaker, K. A. Hoeben, T. Matozaki, G. E. J. Langenbach, G. Kraal, V. Everts, and T. K. van den Berg Inhibitory regulation of osteoclast bone resorption by signal regulatory protein {alpha} FASEB J, December 1, 2009; 23(12): 4081 - 4090. [Abstract] [Full Text] [PDF] B. Tondelli, H. C. Blair, M. Guerrini, K. D. Patrene, B. Cassani, P. Vezzoni, and F. Lucchini Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse Am. J. Pathol., March 1, 2009; 174(3): 727 - 735. [Abstract] [Full Text] [PDF]

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