Restoring T and B cell generation in X-linked severe combined immunodeficiency mice through hematopoietic stem cells adenine base editing.

Autor:	Zhang L; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China., Li K; State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai 200433, China., Liu Z; Cambridge-Suda Genomic Resource Center, Suzhou Medical College of Soochow University, Suzhou 215123, China., An L; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China., Wei H; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China., Pang S; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China., Cao Z; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China., Huang X; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China., Jin X; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China. Electronic address: jinxiaohua@nrifp.org.cn., Ma X; National Research Institute for Family Planning, Beijing 100081, China; National Human Genetic Resources Center, Beijing 102206, China. Electronic address: maxu_fg@nrifp.org.cn.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jun 05; Vol. 32 (6), pp. 1658-1671. Date of Electronic Publication: 2024 Mar 26.
DOI:	10.1016/j.ymthe.2024.03.028
Abstrakt:	Base editing of hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematologic diseases. However, the feasibility of using adenine-base-edited HSPCs for treating X-linked severe combined immunodeficiency (SCID-X1), the influence of dose-response relationships on immune cell generation, and the potential risks have not been demonstrated in vivo. Here, a humanized SCID-X1 mouse model was established, and 86.67% ± 2.52% (n = 3) of mouse hematopoietic stem cell (HSC) pathogenic mutations were corrected, with no single-guide-RNA (sgRNA)-dependent off-target effects detected. Analysis of peripheral blood over 16 weeks post-transplantation in mice with different immunodeficiency backgrounds revealed efficient immune cell generation following transplantation of different amounts of modified HSCs. Therefore, a large-scale infusion of gene-corrected HSCs within a safe range can achieve rapid, stable, and durable immune cell regeneration. Tissue-section staining further demonstrated the restoration of immune organ tissue structures, with no tumor formation in multiple organs. Collectively, these data suggest that base-edited HSCs are a potential therapeutic approach for SCID-X1 and that a threshold infusion dose of gene-corrected cells is required for immune cell regeneration. This study lays a theoretical foundation for the clinical application of base-edited HSCs in treating SCID-X1. Competing Interests: Declaration of interests The authors declare that they have no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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