Advanced

Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia

Debnath, Shubhranshu LU ; Jaako, Pekka LU ; Siva, Kavitha LU ; Rothe, Michael; Chen, Jun LU ; Dahl, Maria LU ; Gaspar, H. Bobby; Flygare, Johan LU ; Schambach, Axel and Karlsson, Stefan LU (2017) In Molecular Therapy 25(8). p.1805-1814
Abstract

Diamond-Blackfan anemia is a congenital erythroid hypoplasia and is associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with Diamond-Blackfan anemia have mutations in a gene encoding ribosomal protein S19 (RPS19). Through overexpression of RPS19 using a lentiviral vector with the spleen focus-forming virus promoter, we demonstrated that the Diamond-Blackfan anemia phenotype can be successfully treated in Rps19-deficient mice. In our present study, we assessed the efficacy of a clinically relevant promoter, the human elongation factor 1α short promoter, with or without the locus control region of the β-globin gene for treatment of RPS19-deficient Diamond-Blackfan anemia. The findings... (More)

Diamond-Blackfan anemia is a congenital erythroid hypoplasia and is associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with Diamond-Blackfan anemia have mutations in a gene encoding ribosomal protein S19 (RPS19). Through overexpression of RPS19 using a lentiviral vector with the spleen focus-forming virus promoter, we demonstrated that the Diamond-Blackfan anemia phenotype can be successfully treated in Rps19-deficient mice. In our present study, we assessed the efficacy of a clinically relevant promoter, the human elongation factor 1α short promoter, with or without the locus control region of the β-globin gene for treatment of RPS19-deficient Diamond-Blackfan anemia. The findings demonstrate that these vectors rescue the proliferation defect and improve erythroid development of transduced RPS19-deficient bone marrow cells. Remarkably, bone marrow failure and severe anemia in Rps19-deficient mice was cured with enforced expression of RPS19 driven by the elongation factor 1α short promoter. We also demonstrate that RPS19-deficient bone marrow cells can be transduced and these cells have the capacity to repopulate bone marrow in long-term reconstituted mice. Our results collectively demonstrate the feasibility to cure RPS19-deficient Diamond-Blackfan anemia using lentiviral vectors with cellular promoters that possess a reduced risk of insertional mutagenesis. Diamond-Blackfan anemia is a congenital erythroid hypoplasia. Twenty-five percent of patients have mutations in a gene encoding ribosomal protein S19. Using an RPS19-deficient mouse model, Debnath et al. demonstrate the feasibility to cure RPS19-deficient Diamond-Blackfan anemia by means of lentiviral vectors with cellular promoters that possess a reduced risk of insertional mutagenesis.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Diamond-Blackfan anemia, Gene therapy, Lentiviral vectors
in
Molecular Therapy
volume
25
issue
8
pages
1805 - 1814
publisher
Nature Publishing Group
external identifiers
  • scopus:85018628916
  • wos:000406989700012
ISSN
1525-0016
DOI
10.1016/j.ymthe.2017.04.002
language
English
LU publication?
yes
id
139d4f4e-67e6-41fb-95f1-2b9b62b9ed32
date added to LUP
2017-05-24 14:21:55
date last changed
2018-01-07 12:05:17
@article{139d4f4e-67e6-41fb-95f1-2b9b62b9ed32,
  abstract     = {<p>Diamond-Blackfan anemia is a congenital erythroid hypoplasia and is associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with Diamond-Blackfan anemia have mutations in a gene encoding ribosomal protein S19 (RPS19). Through overexpression of RPS19 using a lentiviral vector with the spleen focus-forming virus promoter, we demonstrated that the Diamond-Blackfan anemia phenotype can be successfully treated in Rps19-deficient mice. In our present study, we assessed the efficacy of a clinically relevant promoter, the human elongation factor 1α short promoter, with or without the locus control region of the β-globin gene for treatment of RPS19-deficient Diamond-Blackfan anemia. The findings demonstrate that these vectors rescue the proliferation defect and improve erythroid development of transduced RPS19-deficient bone marrow cells. Remarkably, bone marrow failure and severe anemia in Rps19-deficient mice was cured with enforced expression of RPS19 driven by the elongation factor 1α short promoter. We also demonstrate that RPS19-deficient bone marrow cells can be transduced and these cells have the capacity to repopulate bone marrow in long-term reconstituted mice. Our results collectively demonstrate the feasibility to cure RPS19-deficient Diamond-Blackfan anemia using lentiviral vectors with cellular promoters that possess a reduced risk of insertional mutagenesis. Diamond-Blackfan anemia is a congenital erythroid hypoplasia. Twenty-five percent of patients have mutations in a gene encoding ribosomal protein S19. Using an RPS19-deficient mouse model, Debnath et al. demonstrate the feasibility to cure RPS19-deficient Diamond-Blackfan anemia by means of lentiviral vectors with cellular promoters that possess a reduced risk of insertional mutagenesis.</p>},
  author       = {Debnath, Shubhranshu and Jaako, Pekka and Siva, Kavitha and Rothe, Michael and Chen, Jun and Dahl, Maria and Gaspar, H. Bobby and Flygare, Johan and Schambach, Axel and Karlsson, Stefan},
  issn         = {1525-0016},
  keyword      = {Diamond-Blackfan anemia,Gene therapy,Lentiviral vectors},
  language     = {eng},
  number       = {8},
  pages        = {1805--1814},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia},
  url          = {http://dx.doi.org/10.1016/j.ymthe.2017.04.002},
  volume       = {25},
  year         = {2017},
}