TY  - JOUR
UR  - http://doi.org/10.1016/j.ymthe.2017.04.002
SN  - 1525-0024
JF  - Molecular Therapy
A1  - Debnath, S
A1  - Jaako, P
A1  - Siva, K
A1  - Rothe, M
A1  - Chen, J
A1  - Dahl, M
A1  - Gaspar, HB
A1  - Flygare, J
A1  - Schambach, A
A1  - Karlsson, S
VL  - 25
SP  - 1805
IS  - 8
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
N2  - 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 1? short promoter, with or without the locus control region of the ?-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 1? 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.
ID  - discovery1555497
KW  - Diamond-Blackfan anemia
KW  -  gene therapy
KW  -  lentiviral vectors
TI  - Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia
AV  - public
Y1  - 2017/08/02/
EP  - 1814
ER  -