Gene therapy of Diamond Blackfan anemia CD34(+) cells leads to improved erythroid development and engraftment following transplantation

Experimental Hematology
Johan FlygareStefan Karlsson

Abstract

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this study, we asked if RPS19 gene transfer corrects erythroid development in unsorted cells transplanted to immunodeficient mice and if the RPS19-corrected fraction has a proliferative advantage after transplantation. We further determined if high level of RPS19 expression is required for correction. Mobilized peripheral blood CD34(+) cells were transduced by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus envelope. Vectors containing two different promoters with different RPS19 transgene expression levels were compared. Transduced cells were transplanted to immunocompromised nonobese diabetic/severe combined immunodeficient-beta2 microglobulin null mice in order to assess therapeutic effects of RPS19 gene transfer in vivo. We show that correction of erythroid development requires high RPS19 expression. The corrected fraction of unselected DBA cells have a survival advantage in vivo, suggestin...Continue Reading

Citations

Nov 17, 2009·Current Opinion in Pediatrics·Jeffrey M Lipton, Steven R Ellis
May 11, 2010·Advances in Hematology·Deborah Chiabrando, Emanuela Tolosano
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Jan 14, 2010·Current Opinion in Pediatrics

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