Gene therapy cures the anemia and lethal bone marrow failure in mouse model for RPS19-deficient Diamond-Blackfan anemia.

Jaako, PekkaLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Department of Experimental Medical Science,Faculty of Medicine,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine (author)

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 for ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrate 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.

Debnath, ShubhranshuLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)med-sdt (author)
Olsson, KarinLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)molm-kol (author)
Modlich, Ute (author)
Rothe, Michael (author)
Schambach, Axel (author)
Flygare, JohanLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)molm-jfl (author)
Karlsson, StefanLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)molm-ska (author)
Institutionen för experimentell medicinsk vetenskapMedicinska fakulteten (creator_code:org_t)

In:Haematologica: Ferrata Storti Foundation (Haematologica)99:12, s. 1792-17981592-87210390-6078

By the author/editor: Jaako, Pekka; Debnath, Shubhra ...; Olsson, Karin; Modlich, Ute; Rothe, Michael; Schambach, Axel; show more...; Flygare, Johan; Karlsson, Stefan; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

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