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Gene therapy cures the anemia and lethal bone marrow failure in mouse model for RPS19-deficient Diamond-Blackfan anemia.

Jaako, Pekka LU ; Debnath, Shubhranshu LU ; Olsson, Karin LU ; Modlich, Ute; Rothe, Michael; Schambach, Axel; Flygare, Johan LU and Karlsson, Stefan LU (2014) In Haematologica 99(12). p.1792-1798
Abstract
Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25 % of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models for ribosomal protein... (More)
Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25 % of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models for ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrate that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Haematologica
volume
99
issue
12
pages
1792 - 1798
publisher
Ferrata Storti Foundation
external identifiers
  • pmid:25216681
  • wos:000347016400004
  • scopus:84919339897
ISSN
1592-8721
DOI
10.3324/haematol.2014.111195
language
English
LU publication?
yes
id
68c4878a-a554-4f10-b96f-7cdd55be135c (old id 4691692)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25216681?dopt=Abstract
date added to LUP
2014-10-05 20:33:56
date last changed
2017-08-13 03:23:22
@article{68c4878a-a554-4f10-b96f-7cdd55be135c,
  abstract     = {Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25 % of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models for ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrate that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia.},
  author       = {Jaako, Pekka and Debnath, Shubhranshu and Olsson, Karin and Modlich, Ute and Rothe, Michael and Schambach, Axel and Flygare, Johan and Karlsson, Stefan},
  issn         = {1592-8721},
  language     = {eng},
  number       = {12},
  pages        = {1792--1798},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {Gene therapy cures the anemia and lethal bone marrow failure in mouse model for RPS19-deficient Diamond-Blackfan anemia.},
  url          = {http://dx.doi.org/10.3324/haematol.2014.111195},
  volume       = {99},
  year         = {2014},
}