AP-HP. Centre - Université de Paris, Hôpital Cochin, Centre de Référence Maladie Rare - Mucoviscidose.
Université de Paris, Faculté de Médecine.
Curr Opin Pulm Med. 2021 Nov 1;27(6):567-574. doi: 10.1097/MCP.0000000000000827.
Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function and they will benefit most of the patients with cystic fibrosis in the near future. However, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon, and the purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations nonresponsive to CFTR modulators.
These different approaches constitute readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA-based or DNA-based, and cell-based therapies. Some approaches using mRNA or cDNA combined with a delivery vehicle are mutation-agnostic therapies. Other approaches, such as the use of tRNA, antisense oligonucleotides, gene editing or cell-based therapies are mutation-specific therapies.
Most of these approaches are in preclinical development or for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.
囊性纤维化是一种严重的常染色体隐性遗传病，由编码囊性纤维化跨膜电导调节因子（CFTR）蛋白的 CFTR 基因突变引起，CFTR 蛋白是一种在许多上皮细胞中表达的氯离子通道。新型 CFTR 调节剂旨在恢复 CFTR 蛋白的功能，它们将在不久的将来使大多数囊性纤维化患者受益。然而，超过 10%的 CFTR 突变不会产生任何 CFTR 蛋白供 CFTR 调节剂作用，本综述的目的是概述针对对 CFTR 调节剂无反应的突变患者的不同治疗方法。
这些不同的方法包括无意义突变的通读剂、基于核酸的治疗方法、基于 RNA 或 DNA 的治疗方法以及基于细胞的治疗方法。一些使用 mRNA 或 cDNA 结合递送载体的方法是无突变疗法。其他方法，如使用 tRNA、反义寡核苷酸、基因编辑或基于细胞的治疗方法是针对特定突变的治疗方法。
这些方法中的大多数都处于临床前开发阶段，对于其中一些方法，已经进入早期临床阶段。在它们能够安全地转化为患者之前，还有许多障碍和挑战需要解决。
