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Gene therapy of Diamond Blackfan anemia CD34(+) cells leads to improved erythroid development and engraftment following transplantation.

Flygare, Johan LU ; Olsson, Karin LU ; Richter, Johan LU and Karlsson, Stefan LU (2008) In Experimental Hematology 36. p.1428-1435
Abstract
OBJECTIVE: Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this study, we asked if RPS19 gene transfer corrects erythroid development in unsorted cells transplanted to immunodeficient mice and if the RPS19-corrected fraction has a proliferative advantage after transplantation. We further determined if high level of RPS19 expression is required for correction. MATERIAL AND METHODS: Mobilized peripheral blood CD34(+) cells were transduced by oncoretroviral vector particles pseudotyped... (More)
OBJECTIVE: Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this study, we asked if RPS19 gene transfer corrects erythroid development in unsorted cells transplanted to immunodeficient mice and if the RPS19-corrected fraction has a proliferative advantage after transplantation. We further determined if high level of RPS19 expression is required for correction. MATERIAL AND METHODS: Mobilized peripheral blood CD34(+) cells were transduced by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus envelope. Vectors containing two different promoters with different RPS19 transgene expression levels were compared. Transduced cells were transplanted to immunocompromised nonobese diabetic/severe combined immunodeficient-beta2 microglobulin null mice in order to assess therapeutic effects of RPS19 gene transfer in vivo. RESULTS: We show that correction of erythroid development requires high RPS19 expression. The corrected fraction of unselected DBA cells have a survival advantage in vivo, suggesting that successful gene therapy may only require correction of a fraction of the patient cells. CONCLUSION: Our findings are fundamental for development of clinical gene therapy for DBA because they demonstrate increased engraftment of RPS19-transduced cells without selection of gene-corrected cells prior to transplantation, an essential prelude to studying long-term therapeutic effects in emerging animal models for DBA. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
36
pages
1428 - 1435
publisher
Elsevier
external identifiers
  • wos:000260617300003
  • pmid:18715690
  • scopus:53749092159
ISSN
1873-2399
DOI
10.1016/j.exphem.2008.06.012
language
English
LU publication?
yes
id
86402331-9041-446d-8fc1-9e4f3d58b0b4 (old id 1223033)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18715690?dopt=Abstract
date added to LUP
2008-09-03 13:12:10
date last changed
2017-11-19 04:17:24
@article{86402331-9041-446d-8fc1-9e4f3d58b0b4,
  abstract     = {OBJECTIVE: Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this study, we asked if RPS19 gene transfer corrects erythroid development in unsorted cells transplanted to immunodeficient mice and if the RPS19-corrected fraction has a proliferative advantage after transplantation. We further determined if high level of RPS19 expression is required for correction. MATERIAL AND METHODS: Mobilized peripheral blood CD34(+) cells were transduced by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus envelope. Vectors containing two different promoters with different RPS19 transgene expression levels were compared. Transduced cells were transplanted to immunocompromised nonobese diabetic/severe combined immunodeficient-beta2 microglobulin null mice in order to assess therapeutic effects of RPS19 gene transfer in vivo. RESULTS: We show that correction of erythroid development requires high RPS19 expression. The corrected fraction of unselected DBA cells have a survival advantage in vivo, suggesting that successful gene therapy may only require correction of a fraction of the patient cells. CONCLUSION: Our findings are fundamental for development of clinical gene therapy for DBA because they demonstrate increased engraftment of RPS19-transduced cells without selection of gene-corrected cells prior to transplantation, an essential prelude to studying long-term therapeutic effects in emerging animal models for DBA.},
  author       = {Flygare, Johan and Olsson, Karin and Richter, Johan and Karlsson, Stefan},
  issn         = {1873-2399},
  language     = {eng},
  pages        = {1428--1435},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Gene therapy of Diamond Blackfan anemia CD34(+) cells leads to improved erythroid development and engraftment following transplantation.},
  url          = {http://dx.doi.org/10.1016/j.exphem.2008.06.012},
  volume       = {36},
  year         = {2008},
}