Cystic fibrosis (CF) is an autosomal recessive disease caused by variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although CF affects multiple organs, the primary cause of mortality is respiratory failure resulting from poor clearance of hyperviscous secretions and subsequent airway infection. Recently developed CFTR modulators provide significant therapeutic benefit to the majority of CF individuals. However, treatments directed at the underlying cause are needed for the ∼7% of CF patients who are not expected to be responsive to these modulators. Genome editing can restore the native CFTR genetic sequence and function to mutant cells, representing an approach to establish durable physiologic CFTR correction. Although editing the CFTR gene in various airway cell types may transiently restore CFTR activity, effort is focused on editing airway basal stem/progenitor cells, since their correction would allow appropriate and durable expression of CFTR in stem cell-derived epithelial cell types. Substantial progress has been made to directly correct airway basal cells in vitro, theoretically enabling transplantation of autologous corrected cells to regenerate an airway with CFTR functional cells. Another approach to create autologous, gene-edited airway basal cells is derivation of CF donor-specific induced pluripotent stem cells, correction of the CFTR gene, and subsequent directed differentiation to airway basal cells. Further work is needed to translate these advances by developing effective transplantation methods. Alternatively, gene editing in vivo may enable CFTR correction. However, this approach will require robust delivery methods ensuring that basal cells are efficiently targeted and corrected. Recent advances in gene editing-based therapies provide hope that the genetic underpinning of CF can be durably corrected in airway epithelial stem cells, thereby preventing or treating lung disease in all people with CF.

中文翻译：

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气道干细胞校正：治疗囊性纤维化的基因组编辑方法。

囊性纤维化 (CF) 是一种常染色体隐性遗传疾病，由囊性纤维化跨膜传导调节 ( CFTR ) 基因变异引起。尽管 CF 影响多个器官，但死亡的主要原因是由于高粘性分泌物清除不良和随后的气道感染导致的呼吸衰竭。最近开发的 CFTR 调节剂为大多数 CF 个体提供了显着的治疗益处。然而，大约 7% 的 CF 患者需要针对根本原因进行治疗，这些患者预计对这些调节剂没有反应。基因组编辑可以恢复突变细胞的天然CFTR基因序列和功能，代表了一种建立持久生理 CFTR 校正的方法。虽然编辑CFTR各种气道细胞类型中的基因可能会暂时恢复 CFTR 活性，努力集中在编辑气道基底干/祖细胞上，因为它们的校正将允许 CFTR 在干细胞衍生的上皮细胞类型中适当和持久地表达。在体外直接纠正气道基底细胞方面取得了实质性进展，理论上可以移植自体纠正细胞以再生具有 CFTR 功能细胞的气道。另一种创建自体基因编辑气道基底细胞的方法是衍生 CF 供体特异性诱导多能干细胞，校正CFTR基因，随后定向分化为气道基底细胞。需要进一步的工作通过开发有效的移植方法来转化这些进步。或者，体内基因编辑可以实现 CFTR 校正。然而，这种方法将需要强大的传递方法，以确保有效地靶向和纠正基底细胞。基于基因编辑的疗法的最新进展提供了希望，CF 的遗传基础可以在气道上皮干细胞中得到持久纠正，从而预防或治疗所有 CF 患者的肺部疾病。