Advanced

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

Askmyr, Maria LU ; de Vries, Teun J; Schoenmaker, Ton; Ehinger, Mats LU ; Brun, Ann LU ; Fasth, Anders; Karlsson, Stefan LU ; Everts, Vincent and Richter, Johan LU (2007) In Blood 109(12). p.5178-5185
Abstract
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 (tcirg 1) 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 tcirgl and GFP, and subsequently transplanted intraperitoneally to irradiated neonatal... (More)
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 (tcirg 1) 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 tcirgl 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 GFPpositive 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
109
issue
12
pages
5178 - 5185
publisher
American Society of Hematology
external identifiers
  • wos:000247360200027
  • scopus:34250009365
ISSN
1528-0020
DOI
10.1182/blood-2006-12-061382
language
English
LU publication?
yes
id
5badbdd1-f869-4ca6-8fd5-2261de41dad3 (old id 166886)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17332244&dopt=Abstract
date added to LUP
2007-07-11 12:12:07
date last changed
2017-03-12 03:27:13
@article{5badbdd1-f869-4ca6-8fd5-2261de41dad3,
  abstract     = {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 (tcirg 1) 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 tcirgl 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 GFPpositive 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.},
  author       = {Askmyr, Maria and de Vries, Teun J and Schoenmaker, Ton and Ehinger, Mats and Brun, Ann and Fasth, Anders and Karlsson, Stefan and Everts, Vincent and Richter, Johan},
  issn         = {1528-0020},
  language     = {eng},
  number       = {12},
  pages        = {5178--5185},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Hematopoietic stem cell targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice.},
  url          = {http://dx.doi.org/10.1182/blood-2006-12-061382},
  volume       = {109},
  year         = {2007},
}