Gene therapy for cystic fibrosis: Challenges and prospects

Abstract

Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.

Examination of Factors Affecting Site-Directed RNA Editing by the MS2-ADAR1 Deaminase System

“…This limitation can be minimized by transient transfection and optimizing the effector molecule concentration. Indeed, a recent CRISPR-meditated approach to cystic fibrosis therapy approach was based on transient application of a modified CRISPR system to edit the gene encoding cystic fibrosis transmembrane conductance regulator [ 28 ]. dCas13-ADAR fusions for site directed mutagenesis is a powerful technique with higher RNA editing efficiency [ 7 ].…”

ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases

“…However, despite the great potential and the enormous advances made in RNA-based and CRISPR/Cas9-based therapeutic strategies, there are still several issues to overcome, particularly in the field of airway diseases. Among these are the following: being able to find an efficient transgene vector that does not create strong immunogenicity and must be able to penetrate the airways mucus layer, targeting the specific cell type in the complex respiratory system, and maintaining an effect over time that does not cause toxicity [48][49][50]. To date, many trials using RNA-based and DNA-based therapeutics have been done or are in progress.…”

Genetic therapies in cystic fibrosis

“…With permanent treatment strategies such as gene editing actively in preclinical development, semi-permanent nucleic acid-based therapy (NABT) approaches are already entering clinical trials (Table 1). Recent literature reviews of ongoing CF gene therapy research importantly highlight the broad range of genetic therapy efforts in CF, with notable attention to two reviews published in the past year from MacLachlan et al [6 ▪▪ ], and Sui et al [7 ▪▪ ], each of which broadly address both permanent and semipermanent strategies in both preclinical and clinical development. This mini review focuses on the recent advancements of semipermanent NABTs, including deoxyribonucleic acid (DNA) based therapy (i.e., gene delivery) and messenger ribonucleic acid (RNA) delivery, with a particular emphasis on treatment approaches under investigation in very recent or current clinical trials…”