학술논문
Gene editing-based targeted integration for correction of Wiskott-Aldrich syndrome.
Document Type
Academic Journal
Author
Pille M; Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium.; Avila JM; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.; Park SH; Department of Bioengineering, Rice University, Houston, TX, USA.; Le CQ; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.; Xue H; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.; Haerynck F; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium.; Saxena L; Department of Bioengineering, Rice University, Houston, TX, USA.; Lee C; Department of Bioengineering, Rice University, Houston, TX, USA.; Shpall EJ; M.D. Anderson Cancer Center, Houston, TX, USA.; Bao G; Department of Bioengineering, Rice University, Houston, TX, USA.; Vandekerckhove B; Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium.; Davis BR; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101624857 Publication Model: eCollection Cited Medium: Print ISSN: 2329-0501 (Print) Linking ISSN: 23290501 NLM ISO Abbreviation: Mol Ther Methods Clin Dev Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2329-0501
Abstract
Wiskott-Aldrich syndrome (WAS) is a severe X-linked primary immunodeficiency resulting from a diversity of mutations distributed across all 12 exons of the WAS gene. WAS encodes a hematopoietic-specific and developmentally regulated cytoplasmic protein (WASp). The objective of this study was to develop a gene correction strategy potentially applicable to most WAS patients by employing nuclease-mediated, site-specific integration of a corrective WAS gene sequence into the endogenous WAS chromosomal locus. In this study, we demonstrate the ability to target the integration of WAS 2-12 -containing constructs into intron 1 of the endogenous WAS gene of primary CD34 + hematopoietic stem and progenitor cells (HSPCs), as well as WASp-deficient B cell lines and WASp-deficient primary T cells. This intron 1 targeted integration (TI) approach proved to be quite efficient and restored WASp expression in treated cells. Furthermore, TI restored WASp-dependent function to WAS patient T cells. Edited CD34 + HSPCs exhibited the capacity for multipotent differentiation to various hematopoietic lineages in vitro and in transplanted immunodeficient mice. This methodology offers a potential editing approach for treatment of WAS using patient's CD34 + cells.
Competing Interests: The authors declare no competing interests.
(© 2024 The Authors.)
Competing Interests: The authors declare no competing interests.
(© 2024 The Authors.)