Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice.

Gene Therapy
Andrea SchejtmanGiorgia Santilli

Abstract

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic NADPH oxidase, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91phox subunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47phox-deficient CGD, caused by mutations in NCF1, which encodes the p47phox cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47phox lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47phox vector efficiently restores p47phox expression and biochemical NADPH oxidase function in p47phox-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47phox-null mice with Salmonella Typhimurium, a leading cause of sepsis in CGD patients, and found that mice reconstituted with lentivirus-transduced h...Continue Reading

References

Jan 11, 2007·The Journal of Cell Biology·Tobias A FuchsArturo Zychlinsky
Apr 22, 2009·PloS One·J Merlijn van den BergTaco W Kuijpers
Oct 28, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Giorgia SantilliAdrian J Thrasher
Nov 4, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Manuel GrezAdrian J Thrasher
Dec 31, 2010·The New England Journal of Medicine·Douglas B KuhnsJohn I Gallin
Jul 27, 2011·Journal of Clinical Immunology·Fatemeh FattahiMostafa Moin
Mar 16, 2013·Human Gene Therapy Methods·Christian BrendelUlrich Siler
Aug 6, 2013·The Journal of Allergy and Clinical Immunology·Mustafa Yavuz KökerDirk Roos
May 30, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maria ChiriacoAlessandro Aiuti
Oct 8, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Randall K MerlingHarry L Malech
Dec 30, 2014·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Beatriz E MarcianoSteven M Holland
Feb 9, 2016·The Journal of Allergy and Clinical Immunology·Maren WeisserManuel Grez
Mar 30, 2017·The Journal of Experimental Medicine·David C ThomasKenneth G C Smith
May 22, 2017·The Journal of Allergy and Clinical Immunology·Beatriz E MarcianoSteven M Holland
Apr 10, 2018·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Asaf D YanirCaridad A Martinez
May 11, 2018·Journal of the Pediatric Infectious Diseases Society·N L RiderC B Creech
May 11, 2018·Journal of the Pediatric Infectious Diseases Society·Michael D KellerHarry L Malech
May 11, 2018·Journal of the Pediatric Infectious Diseases Society·James A ConnellyJulie-An Talano
Oct 13, 2018·The Journal of Allergy and Clinical Immunology·David C ThomasKenneth G C Smith
Oct 27, 2018·Nature Communications·Gudny A ArnadottirKari Stefansson
Apr 10, 2019·Scandinavian Journal of Immunology·Shaghayegh TajikZahra Pourpak
Jan 29, 2020·Nature Medicine·Donald B KohnUNKNOWN Net4CGD consortium

❮ Previous
Next ❯

Citations

Dec 19, 2020·British Journal of Haematology·Thomas A Fox, Claire Booth

❮ Previous
Next ❯

Methods Mentioned

BETA
FACS
flow cytometry
PMA

Related Concepts

Related Feeds

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

Related Papers

The Journal of Experimental Medicine
S H JacksonS M Holland
Current Opinion in Immunology
Paul G HeyworthJ T Curnutte
Archivum Immunologiae Et Therapiae Experimentalis
Monika JurkowskaJerzy Bal
© 2022 Meta ULC. All rights reserved