Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

Abstract

Prognosis of patients with cystic fibrosis (CF) varies extensively despite recent advances in targeted therapies that improve CF transmembrane conductance regulator (CFTR) function. Despite being a multi-organ disease, extensive lung tissue destruction remains the major cause of morbidity and mortality. Progress towards a curative treatment strategy that implements a CFTR gene addition-technology to the patients’ lungs has been slow and not yet developed beyond clinical trials. Improved delivery vectors are needed to overcome the body’s defense system and ensure an efficient and consistent clinical response before gene therapy is suitable for clinical care. Cell-based therapy–which relies on functional modification of allogenic or autologous cells ex vivo, prior to transplantation into the patient–is now a therapeutic reality for various diseases. For CF, pioneering research has demonstrated proof-of-principle for allogenic transplantation of cultured human airway stem cells into mouse airways. However, applying a cell-based therapy to the human airways has distinct challenges. We review CF gene therapies using viral and non-viral delivery strategies and discuss current advances towards autologous cell-based therapies. Progress towards identification, correction, and expansion of a suitable regenerative cell, as well as refinement of pre-cell transplant lung conditioning protocols is discussed.

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

“…Need to control the phenotype of corrected cells: type of cells, free of new mutation; safe and effective manner to engraft corrected cells into airways [45][46][47][48][49] Ataluren is a non-aminoglycoside small molecule with readthrough properties in vitro that has failed to show in vivo efficacy in phase 3 trials in cystic fibrosis [17]. More recently, ELX-02, a small eukaryotic ribosomal selective glycoside, derived from the initial glycoside core, has shown promise as a PTC readthrough therapeutic and is currently investigated in phase 2 trials in patients with cystic fibrosis caused by the G542X mutant [18].…”

“…First, cells from a patient with cystic fibrosis are isolated and manipulated in the laboratory to reprogramme them into iPSCs; then, the CFTR mutation is converted to the wildtype status, and finally, the corrected iPSCs are turned into basal airway stem cells which have the capacity to differentiate into all cell types of pseudostratified airway epithelium [46]. The last step is to engraft corrected basal cells onto the patient's basement membrane of the airway epithelium to achieve an autologous graft and replenish the airways with a fully CFTR-corrected airway epithelium [47]. Major challenges are the need to derive a pure population of airway epithelial cells from iPSCs in sufficient numbers to engraft in human airways, engrafting these cells in airways in a safe and effective manner and making sure that the corrected cells are free of integrations and somatic mutations [48].…”

“…They have been shown to be well-tolerated in several clinical trials in cystic fibrosis, but their efficacy was limited. Other nonviral vectors such as lipid nanoparticles or exosomes are being worked on [47]. Exosomes are extracellular vesicles secreted by cells and carrying proteins, lipids or the mRNA of neighbouring or distant cells [57].…”

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

“…Moreover, it has been demonstrated that the inhibition of NMD by small molecules (SMG1i or NMDI-14) or antisense oligonucleotides (ASOs), in combination with G418 and/or CFTR modulators, rescued W1282X-CFTR function in the 16HBE cell line and primary nasal epithelial cells [30,[32][33][34]. Moreover, gene and stem cell-based therapy or genome editing by CRISPR-Cas9 are being explored in in vitro studies as therapeutic approaches for CF patients bearing nonsense mutations [35][36][37][38][39][40].…”

Gene therapy for cystic fibrosis: Challenges and prospects

“…New animal models and more efficacious gene transfer agents have been developed to move the field in the path to success. Several recent excellent review articles have summarized and discussed the lessons and achievements from the last 3 decades ( Cooney et al, 2018a ; Donnelley and Parsons, 2018 ; Yan et al, 2019 ; Tang et al, 2020a ; Allan et al, 2021 ; Lee et al, 2021 ). In this review, after a brief description of the lessons learned from the previous unsuccessful clinical trials of CF gene therapy in an alignment with recent progress in animal models and viral vectors as tools of gene delivery, we will focus on the major challenges to the implementation of the gene therapy for CF lung disease.…”