美国加州大学洛杉矶分校Donald B. Kohn团队发现，通过腺嘌呤碱基编辑可恢复CD3δ严重联合免疫缺陷患者的T细胞生成。该项研究成果于2023年3月20日在线发表在《细胞》杂志上。
研究人员展示了一种腺嘌呤碱基编辑（ABE）策略来恢复自体造血干细胞和祖细胞（HSPC）的CD3δ。将编码实验室进化的ABE mRNA和向导RNA送入一个CD3δ SCID患者的HSPC中，导致了71.2%±7.85%（n=3）的致病突变纠正。经过编辑的HSPC在人工胸腺器官中分化，产生了成熟的T细胞，表现出不同的TCR复合物和TCR依赖功能。经过编辑的人类HSPC移植到免疫缺陷小鼠体内，16周后，研究人员从小鼠骨髓中分离出的人类CD34+细胞的CD3D缺陷有88%得以逆转，这表明长期再繁殖的造血干细胞得到了纠正。这些发现证明了ABE在HSPC中治疗CD3δ SCID的临床前疗效，并为开发CD3δ SCID患者的一次性治疗奠定了基础。
据介绍，CD3δ SCID是一种毁灭性的先天性免疫错误，由CD3D的突变引起，其编码正常胸腺造血所必需的CD3/TCR复合物的不变CD3δ链。
附：英文原文
Title: Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing
Author: Grace E. McAuley, Gloria Yiu, Patrick C. Chang, Gregory A. Newby, Beatriz Campo-Fernandez, Sorel T. Fitz-Gibbon, Xiaomeng Wu, Sung-Hae L. Kang, Amber Garibay, Jeffrey Butler, Valentina Christian, Ryan L. Wong, Kelcee A. Everette, Anthony Azzun, Hila Gelfer, Christopher S. Seet, Aru Narendran, Luis Murguia-Favela, Zulema Romero, Nicola Wright, David R. Liu, Gay M. Crooks, Donald B. Kohn
Issue&Volume: 2023-03-20
Abstract: CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis.We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologoushematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolvedABE and guide RNA into a CD3δ SCID patient’s HSPCs resulted in a 71.2% ± 7.85% (n =3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificialthymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependentfunctions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversionof the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicatingcorrection of long-term repopulating HSCs. These findings demonstrate the preclinicalefficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation forthe development of a one-time treatment for CD3δ SCID patients.
DOI: 10.1016/j.cell.2023.02.027
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00170-8