%0 Journal Article
%@ 1525-0024
%A Debnath, S
%A Jaako, P
%A Siva, K
%A Rothe, M
%A Chen, J
%A Dahl, M
%A Gaspar, HB
%A Flygare, J
%A Schambach, A
%A Karlsson, S
%D 2017
%F discovery:1555497
%J Molecular Therapy
%K Diamond-Blackfan anemia, gene therapy, lentiviral vectors
%N 8
%P 1805-1814
%T Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia
%U https://discovery.ucl.ac.uk/id/eprint/1555497/
%V 25
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.