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:
https://lup.lub.lu.se/record/166886
- author
- 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
- organization
- publishing date
- 2007
- 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
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Molecular Medicine and Gene Therapy (013022010), Pathology, (Lund) (013030000)
- 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
- 2016-04-01 11:51:39
- date last changed
- 2022-04-28 21:06:41
@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 = {{https://lup.lub.lu.se/search/files/2675093/625909.pdf}},
doi = {{10.1182/blood-2006-12-061382}},
volume = {{109}},
year = {{2007}},
}