Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice
| Autor: | Stefan Karlsson, Maria K. Johansson, Anders Fasth, Vincent Everts, Teun J. de Vries, Johan Richter, Ann C.M. Brun, Mats Ehinger, Ton Schoenmaker |
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| Přispěvatelé: | Orale Celbiologie (OUD, ACTA), Parodontologie (OUD, ACTA) |
| Rok vydání: | 2007 |
| Předmět: |
Pathology
medicine.medical_specialty Vacuolar Proton-Translocating ATPases medicine.medical_treatment Immunology Hematopoietic stem cell transplantation Biology Biochemistry Bone resorption Andrology TCIRG1 Mice medicine Animals Sequence Deletion Hematopoietic Stem Cell Transplantation Hematopoietic stem cell Osteopetrosis Cell Biology Genetic Therapy Hematology medicine.disease Mice Mutant Strains Transplantation Survival Rate medicine.anatomical_structure Animals Newborn Disease Progression Stem cell Infantile malignant osteopetrosis |
| Zdroj: | Johansson, M K, de Vries, T J, Schoenmaker, A M, Ehinger, M, Brun, A C, Fasth, A, Karlsson, S, Everts, V & Richter, J 2007, ' Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice ', Blood, vol. 109, pp. 5178-5185 . https://doi.org/10.1182/blood-2006-12-061382 Blood, 109, 5178-5185. American Society of Hematology Blood; 109(12), pp 5178-5185 (2007) |
| ISSN: | 0006-4971 1528-0020 |
| DOI: | 10.1182/blood-2006-12-061382 |
| Popis: | 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 (tcirg1) and die at 3 to 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 intraperitoneally to irradiated neonatal oc/oc mice. Eight of 15 mice survived past the normal life span 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 toward the development of gene therapy for osteopetrosis. |
| Databáze: | OpenAIRE |
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