title: Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia.
abstract: 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.
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
authors.forename: Pekka
authors.initials: P
authors.lastname: Jaako
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
authors.forename: Shubhranshu
authors.initials: S
authors.lastname: Debnath
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
authors.forename: Karin
authors.initials: K
authors.lastname: Olsson
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Germany; LOEWE Research Group for Gene Modification in Stem Cells, Paul-Ehrlich-Institute, 63225 Langen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Modlich
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Germany;
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden;
authors.forename: Johan
authors.initials: J
authors.lastname: Flygare
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund University, Sweden; Stefan.Karlsson@med.lu.se.
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000741:Anemia, Aplastic; D029503:Anemia, Diamond-Blackfan / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C040343:ribosomal protein S19