Efficient retrovirus-mediated PIG-A gene transfer and stable restoration of GPI-anchored protein expression in cells with the PNH phenotype.

Blood
Nishimura JiC A Smith

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder characterized by complement-mediated hemolysis due to deficiencies of glycosylphosphatidylinositol-anchored proteins (GPI-APs) in subpopulations of blood cells. Acquired mutations in the X-linked phosphatidylinositol glycan-class A (PIG-A) gene appear to be the characteristic and pathogenetic cause of PNH. To develop a gene therapy approach for PNH, a retroviral vector construct, termed MPIN, was made containing the PIG-A complementary DNA along with an internal ribosome entry site and the nerve growth factor receptor (NGFR) as a selectable marker. MPIN transduction led to efficient and stable PIG-A and NGFR gene expression in a PIG-A-deficient B-cell line (JY5), a PIG-A-deficient K562 cell line, an Epstein-Barr virus-transformed B-cell line (TK-14(-)) established from a patient with PNH, as well as peripheral blood (PB) mononuclear cells from a patient with PNH. PIG-A expression in these cell lines stably restored GPI-AP expression. MPIN was transduced into bone marrow mononuclear cells from a patient with PNH, and myeloid/erythroid colonies and erythroid cells were derived. These transduced erythroid cells restored surface expression of GPI...Continue Reading

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Citations

Mar 12, 2003·International Journal of Hematology·Wendell F Rosse, Junichi Nishimura
Mar 12, 2003·International Journal of Hematology·Gabrielle Meyers, Charles J Parker
Feb 13, 2007·Paediatric Drugs·Marry M van den Heuvel-Eibrink
Jun 19, 2004·Platelets·Martin GrünewaldMario Koksch
Apr 27, 2010·Toxicon : Official Journal of the International Society on Toxinology·Carl-Wilhelm Vogel, David C Fritzinger
Feb 3, 2005·British Journal of Haematology·M M van den Heuvel-EibrinkE T Korthof
Mar 26, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Birgit EisenhaberFrank Eisenhaber
Jul 27, 2014·Molecular Immunology·Carl-Wilhelm VogelDavid C Fritzinger
Apr 2, 2003·Molecular Therapy : the Journal of the American Society of Gene Therapy·David RobertFrançois Moreau-Gaudry
Nov 25, 2004·Hematology·Wendell F RosseAlan D Schreiber
Sep 10, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Wouter L W HazenbosTaroh Kinoshita

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