Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia
Pekka Jaako,
Shubhranshu Debnath,
Karin Olsson,
Ute Modlich,
Michael Rothe,
Axel Schambach,
Johan Flygare,
Stefan Karlsson
Affiliations
Pekka Jaako
Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
Shubhranshu Debnath
Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
Karin Olsson
Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
Ute Modlich
Institute of Experimental Hematology, Hannover Medical School, Germany;;LOEWE Research Group for Gene Modification in Stem Cells, Paul-Ehrlich-Institute, 63225 Langen, Germany
Michael Rothe
Institute of Experimental Hematology, Hannover Medical School, Germany;
Axel Schambach
Institute of Experimental Hematology, Hannover Medical School, Germany;
Johan Flygare
Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
Stefan Karlsson
Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25% of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models of ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrated that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia.