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Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector

Liu, Yang LU ; Dahl, Maria LU ; Debnath, Shubhranshu LU ; Rothe, Michael ; Smith, Emma LU ; Tan Grahn, Hooi Min LU orcid ; Warsi, Sarah LU ; Chen, Jun LU ; Flygare, Johan LU and Schambach, Axel , et al. (2022) In Haematologica 107(2). p.446-456
Abstract
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder in which pure red blood cell aplasia is associated with physical malformations and a predisposition to cancer. Twentyfive percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene, self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1a short promoter, which can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy... (More)
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder in which pure red blood cell aplasia is associated with physical malformations and a predisposition to cancer. Twentyfive percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene, self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1a short promoter, which can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice long-term and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Haematologica
volume
107
issue
2
pages
446 - 456
publisher
Ferrata Storti Foundation
external identifiers
  • scopus:85105385598
  • pmid:33440921
ISSN
1592-8721
DOI
10.3324/haematol.2020.269142
language
English
LU publication?
yes
id
96b610ba-38de-4bbb-96ec-cbb7025784f4
date added to LUP
2022-11-11 23:16:09
date last changed
2024-02-18 09:50:27
@article{96b610ba-38de-4bbb-96ec-cbb7025784f4,
  abstract     = {{Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder in which pure red blood cell aplasia is associated with physical malformations and a predisposition to cancer. Twentyfive percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene, self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1a short promoter, which can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice long-term and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients.}},
  author       = {{Liu, Yang and Dahl, Maria and Debnath, Shubhranshu and Rothe, Michael and Smith, Emma and Tan Grahn, Hooi Min and Warsi, Sarah and Chen, Jun and Flygare, Johan and Schambach, Axel and Karlsson, Stefan}},
  issn         = {{1592-8721}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{446--456}},
  publisher    = {{Ferrata Storti Foundation}},
  series       = {{Haematologica}},
  title        = {{Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector}},
  url          = {{http://dx.doi.org/10.3324/haematol.2020.269142}},
  doi          = {{10.3324/haematol.2020.269142}},
  volume       = {{107}},
  year         = {{2022}},
}