Gene Therapy: A Possible Alternative to CFTR Modulators?

Abstract

Cystic fibrosis (CF) is a rare genetic disease that affects several organs, but lung disease is the major cause of morbidity and mortality. The gene responsible for CF, the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, has been discovered in 1989. Since then, gene therapy i.e., defective gene replacement by a functional one, remained the ultimate goal but unfortunately, it has not yet been achieved. However, patients care and symptomatic treatments considerably increased CF patients’ life expectancy ranging from 5 years old in the 1960s to 40 today. In the last decade, research works on CFTR protein structure and activity led to the development of new drugs which, by readdressing CFTR to the plasma membrane (correctors) or by enhancing its transport activity (potentiators), allow, alone or in combination, an improvement of CF patients’ lung function and quality of life. While expected, it is not yet known whether taking these drugs from an early age and for years will improve the quality of life of CF patients in the long term and further increase their life expectancy. Besides, these molecules are not available (specific variants of CFTR) or accessible (national health policies) for all patients and there is still no curative treatment. Another alternative that could benefit from new technologies, such as gene therapy, is therefore still attractive, although it is not yet offered to patients. Faced with the development of new CFTR correctors and potentiators, the question arises as to whether there is still a place for gene therapy and this is discussed in this perspective.

No one left behind: review of precision medicine and cystic fibrosis—how the changing approach to cystic fibrosis treatment might lead to tailored therapies for all

“…More specifically, gene therapy aims to supply normal CFTR DNA to affected cells, whereas gene editing would use the cell's own repair mechanisms to correct the defective variants. To our knowledge, CF gene therapy clinical trials have not been associated with improved outcomes, with a weak effect observed on lung function (76). Multiple gene editing tools have been developed and studied in CF, including the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 approach to base editing and prime editing (73).…”

Repeat or single-dose lentiviral vector administration to mouse lungs? It’s all about the timing

“…The introduction of CFTR modulators that act to correct and/or potentiate CFTR channel function has provided substantial clinical benefit to many individuals living with CF. However, not everyone with CF is eligible for these modulator therapies, with 10% of the CF population carrying rare CFTR variants left without an effective treatment [ 2 ]. There is also a high cost associated with these daily pharmaceuticals, with several national health systems declining to recommend government financial support to provide CFTR modulators [ 3 ].…”

Gene therapy for cystic fibrosis: Challenges and prospects

“…As the mutation-agnostic, gene therapy is suitable for all patients with CF, regardless of their genotype ( Griesenbach et al, 2016 ). Thus, gene therapy for CF lung disease remains an attractive approach for treating all the population with CF, not only for other currently lacked of the option of CFTR modulator therapy ( Choi and Engelhardt, 2021 ; Mercier et al, 2021 ). The goal for gene therapy as a cure for CF lung disease has been pursuing for almost 30 years, desirable outcome has not yet met.…”