Utilizing epigenetic regulators to improve HSC-based lentiviral gene therapy.

Autor:	Tajer P; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Karakaslar EO; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.; Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands., Canté-Barrett K; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Naber BAE; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Vloemans SA; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., van Eggermond MCJA; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., van der Hoorn ML; Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands., van den Akker E; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.; Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, The Netherlands., Pike-Overzet K; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands., Staal FJT; Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Sep 24; Vol. 8 (18), pp. 4936-4947.
DOI:	10.1182/bloodadvances.2024013047
Abstrakt:	Abstract: The curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven in various diseases. However, the low number of true HSCs that can be collected from patients and the subsequent in vitro maintenance and expansion of true HSCs for genetic correction remains challenging. Addressing this issue, we here focused on optimizing culture conditions to improve ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explored the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The histone deacetylase inhibitor quisinostat and bromodomain inhibitor CPI203 each promoted ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single-cell RNA sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, whereas the addition of quisinostat or CPI203 improved the expansion of HSCs in transduction protocols. Notably, we demonstrated that the addition of quisinostat improved the LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effects of epigenetic regulators in HSC biology and their clinical applications to advance HSC-based gene correction. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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