Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells

C Petrillo, LG Thorne, G Unali, G Schiroli, AMS Giordano, F Piras, I Cuccovillo, SJ Petit, F Ahsan, M Noursadeghi, S Clare, P Genovese, B Gentner, L Naldini, GJ Towers, A Kajaste-Rudnitski

Research output: Contribution to journalArticle

Abstract

Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry. Importantly, individual variability in endogenous IFITM3 levels correlated with permissiveness of HSCs to lentiviral transduction, suggesting that CsH treatment will be useful for improving ex vivo gene therapy and standardizing HSC transduction across patients. Overall, our work unravels the involvement of innate pathogen recognition molecules in immune blocks to gene correction in primary human HSCs and highlights how these roadblocks can be overcome to develop innovative cell and gene therapies. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)820-832
Number of pages13
JournalCell Stem Cell
Volume23
Issue number6
DOIs
Publication statusPublished - 2018

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Hematopoietic Stem Cells
Genetic Therapy
Interferons
Permissiveness
Cell Engineering
Investigational Therapies
Genetic Engineering
Immunologic Factors
Cell- and Tissue-Based Therapy
Glycoproteins
Proteins
Genes
Gene Editing
cyclosporin H
Therapeutics

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Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells. / Petrillo, C; Thorne, LG; Unali, G; Schiroli, G; Giordano, AMS; Piras, F; Cuccovillo, I; Petit, SJ; Ahsan, F; Noursadeghi, M; Clare, S; Genovese, P; Gentner, B; Naldini, L; Towers, GJ; Kajaste-Rudnitski, A.

In: Cell Stem Cell, Vol. 23, No. 6, 2018, p. 820-832.

Research output: Contribution to journalArticle

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AU - Schiroli, G

AU - Giordano, AMS

AU - Piras, F

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