Prostaglandin E2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells

Molecular Therapy : the Journal of the American Society of Gene Therapy
Garrett C HeffnerGabor Veres

Abstract

Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34+ hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E2 (PGE2) as a positive mediator of lentiviral transduction of CD34+ cells. Supplementation with PGE2 increased lentiviral vector (LVV) transduction of CD34+ cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34+ cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE2 increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE2 improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE2 may be useful in clinical gene therapy applications using lentivirally modified HSPCs.

Citations

Feb 1, 2019·Molecular Diagnosis & Therapy·Valentina GhiaccioLaura Breda
Jul 20, 2019·Human Molecular Genetics·Yasuhiro IkawaMarina Cavazzana
Jul 15, 2020·Gene Therapy·Francesco Piras, Anna Kajaste-Rudnitski
Mar 13, 2019·Nature Reviews. Drug Discovery·Marina CavazzanaEmmanuelle Six
Oct 8, 2020·Biomaterials Science·Kübra Kaygisiz, Christopher V Synatschke
Dec 18, 2020·Frontiers in Immunology·Anna VillaMaria Carmina Castiello
Dec 12, 2020·Nature Reviews. Genetics·Giuliana FerrariAlessandro Aiuti
Feb 5, 2021·Journal of Clinical Medicine·Christi T Salisbury-Ruf, Andre Larochelle
Aug 14, 2018·Molecular Therapy. Methods & Clinical Development·Mor NgomRichard Keith Humphries
May 3, 2021·Journal of Hematology & Oncology·Ying GongWilfred T V Germeraad
May 28, 2021·Gene Therapy·Pervinder Sagoo, H Bobby Gaspar
Apr 18, 2020·Molecular Therapy. Methods & Clinical Development·Ying GongWilfred T V Germeraad
Sep 13, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Byung-Chul LeeCynthia E Dunbar

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Methods Mentioned

BETA
genetic modification
transgenic
flow cytometry
PCR

Software Mentioned

bowtie2
ENSEMBL
LC Solution
FlowJo

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