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)
- author
- 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
- organization
- publishing date
- 2017
- 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
-
- pmid:28434866
- wos:000406989700012
- scopus:85018628916
- 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
- 2025-10-14 13:10:28
@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}},
keywords = {{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}},
doi = {{10.1016/j.ymthe.2017.04.002}},
volume = {{25}},
year = {{2017}},
}