Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Abstract

Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 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 many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical 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.

Keywords: CFTR modulators; RNA therapy; cell-based therapy; cystic fibrosis; gene editing; gene therapy; readthrough agents.

Figure 1

Different strategies of direct in vivo delivery of nucleic acid-based therapies in cystic fibrosis: modified nucleic acids combined or not to a delivery vehicle are administered in vivo in patients.

Figure 2

Main steps for cell-based therapy in cystic fibrosis: it is an ex vivo approach wherein patient’s cells are collected and modified in vitro to obtain corrected basal airway stem cells and then transferred back into the patient.