Barillà Cristina, Suzuki Shingo, Rab Andras, Sorscher Eric J, Davis Brian R
Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
Front Genome Ed. 2022 Mar 7;4:847645. doi: 10.3389/fgeed.2022.847645. eCollection 2022.
Cystic Fibrosis (CF) is caused by a diverse set of mutations distributed across the approximately 250 thousand base pairs of the gene locus, of which at least 382 are disease-causing (CFTR2.org). Although a variety of editing tools are now available for correction of individual mutations, a strong justification can be made for a more universal gene insertion approach, in principle capable of correcting virtually all mutations. Provided that such a methodology is capable of efficiently correcting relevant stem cells of the airway epithelium, this could potentially provide life-long correction for the lung. In this Perspective we highlight several requirements for efficient gene insertion into airway epithelial stem cells. In addition, we focus on specific features of the transgene construct and the endogenous locus that influence whether the inserted gene sequences will give rise to robust and physiologically relevant levels of CFTR function in airway epithelium. Finally, we consider how gene insertion methodologies may be adapted for direct editing.
囊性纤维化（CF）由分布在该基因座约25万个碱基对中的多种突变引起，其中至少382种是致病突变（CFTR2.org）。尽管现在有多种编辑工具可用于纠正单个突变，但原则上能够纠正几乎所有突变的更通用的基因插入方法有充分的理由。只要这种方法能够有效纠正气道上皮的相关干细胞，就有可能为肺部提供终身纠正。在这篇观点文章中，我们强调了将基因有效插入气道上皮干细胞的几个要求。此外，我们关注转基因构建体和内源性基因座的特定特征，这些特征会影响插入的基因序列是否会在气道上皮中产生强大且与生理相关水平的CFTR功能。最后，我们考虑基因插入方法如何适用于直接编辑。
