%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.