Since the CFTR gene was identified in 1989, genomic science has allowed researchers to understand at a molecular level how the normal CFTR protein attains its structure, how it functions, and how its structure and function are altered by CFTR mutations. Classes of mutations have been established according to their effects on the maturation and function of the CFTR protein. Genotype-specific small-molecule drugs aiming at improving the mutant CFTR function have been developed. In 2012 the first CFTR modulator, ivacaftor, was approved for marketing in the US. It is approved for very specific mutations making ivacaftor the first precision medicine for CF, i.e. medicine that is prescribed in individuals with specific molecular biomarkers. Another drug has since been approved (lumacaftor in combination with ivacaftor) for patients bearing two F508del mutations which are present in approximately 40–45% patients with CF. Others are in development to increase the correction of the CFTR protein and/or to treat patients bearing other genotypes.
Other strategies, are also in development to target the basic defects in CF. One approach is to treat CF at a basic level by using oligonucleotides, as in gene therapy, gene editing or mRNA repair. Another approach is to bypass the dysfunctional CFTR protein by activating or inhibiting other ion channels [Brodlie et al., 2015; Griesenbach and Alton, 2015; Solomon et al., 2015; Bosch and De Boeck, 2016; Veit et al., 2016].
Find out how the various CFTR modulating drugs work. Which one offers the best survival?
Oligonucleotide-based approaches aim to bring the normal CFTR gene into the cell or to repair the DNA or RNA, leading to functional CFTR proteins.
Several treatments exist that target areas other than the CFTR protein, such as activators of alternative chloride channels which compensate for CFTR dysfunction.