Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Center for Cystic Fibrosis and Airways Disease Research, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Expert Opin Pharmacother. 2023 Sep-Dec;24(14):1545-1565. doi: 10.1080/14656566.2023.2230129. Epub 2023 Jul 3.
Cystic fibrosis (CF), a potentially fatal genetic disease, is caused by loss-of-function mutations in the gene encoding for the CFTR chloride/bicarbonate channel. Modulator drugs rescuing mutant CFTR traffic and function are now in the clinic, providing unprecedented breakthrough therapies for people with CF (PwCF) carrying specific genotypes. However, several CFTR variants are unresponsive to these therapies.
We discussed several therapeutic approaches that are under development to tackle the fundamental cause of CF, including strategies targeting defective CFTR mRNA and/or protein expression and function. Alternatively, defective chloride secretion and dehydration in CF epithelia could be restored by exploiting pharmacological modulation of alternative targets, i.e., ion channels/transporters that concur with CFTR to maintain the airway surface liquid homeostasis (e.g., ENaC, TMEM16A, SLC26A4, SLC26A9, and ATP12A). Finally, we assessed progress and challenges in the development of gene-based therapies to replace or correct the mutant CFTR gene.
CFTR modulators are benefiting many PwCF responsive to these drugs, yielding substantial improvements in various clinical outcomes. Meanwhile, the CF therapy development pipeline continues to expand with the development of novel CFTR modulators and alternative therapeutic strategies with the ultimate goal of providing effective therapies for all PwCF in the foreseeable future.
囊性纤维化（CF）是一种潜在致命的遗传性疾病，由编码 CFTR 氯离子/碳酸氢盐通道的基因突变引起。现在，能够恢复突变 CFTR 转运和功能的调节剂药物已在临床上使用，为携带特定基因型的 CF 患者（PwCF）提供了前所未有的突破性治疗方法。然而，有几种 CFTR 变体对这些治疗方法没有反应。
我们讨论了几种正在开发的治疗方法，旨在解决 CF 的根本原因，包括针对有缺陷的 CFTR mRNA 和/或蛋白表达和功能的策略。或者，可以通过药理学调节替代靶点来恢复 CF 上皮中缺陷的氯离子分泌和脱水，即与 CFTR 共同维持气道表面液体动态平衡的离子通道/转运体（例如 ENaC、TMEM16A、SLC26A4、SLC26A9 和 ATP12A）。最后，我们评估了基因治疗方法的开发进展和挑战，以替代或纠正突变的 CFTR 基因。
CFTR 调节剂使许多对这些药物有反应的 PwCF 受益，在各种临床结果方面都取得了显著改善。与此同时，CF 治疗开发管道继续扩大，新型 CFTR 调节剂和替代治疗策略的开发，最终目标是在可预见的未来为所有 PwCF 提供有效的治疗方法。
