Advances in the Cystic Fibrosis Drug Development Pipeline

Abstract

Cystic fibrosis is a genetic disease that results in progressive multi-organ manifestations with predominance in the respiratory and gastrointestinal systems. The significant morbidity and mortality seen in the CF population has been the driving force urging the CF research community to further advance treatments to slow disease progression and, in turn, prolong life expectancy. Enormous strides in medical advancements have translated to improvement in quality of life, symptom burden, and survival; however, there is still no cure. This review discusses the most current mainstay treatments and anticipated therapeutics in the CF drug development pipeline within the mechanisms of mucociliary clearance, anti-inflammatory and anti-infective therapies, restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) protein (also known as highly effective modulator therapy (HEMT)), and genetic therapies. Ribonucleic acid (RNA) therapy, gene transfer, and gene editing are being explored in the hopes of developing a treatment and potential cure for people with CF, particularly for those not responsive to HEMT.

Keywords: anti-inflammatory; antibiotics; bacteriophage; cystic fibrosis (CF); cystic fibrosis transmembrane conductance regulator (CFTR); gene-based therapy; highly effective modulator therapy (HEMT); mucolytic therapy.

Figure 1

Reproduced with permission of the Cystic Fibrosis Foundation, Bethesda, Maryland. © July 2023.

Figure 2

Under normal circumstances, translation is halted at stop or “nonsense codons” resulting in a truncated, non-functional CFTR protein. ELX-02 promotes continued translation in spite of such stop codons and increases the probability of full-length CFTR production [16].

Figure 3

Mechanism of SRI-37240. By binding termination factors (black dots) and preventing their normal interaction with translational machinery at stop or “nonsense” codons, SRI-37240 (green boxes) increases the production of full length, and therefore fully functional, CFTR proteins [15].

Figure 4

Simplified schematic of zinc finger nuclease (ZFN) and CRISPR/CAS9 technology: Both systems rely on the use of nucleases (green brackets) to remove mutations in the CFTR gene. Endogenous DNA repair pathways are then able to replace the removed genetic material with wild type nucleotides (small blue boxes).