This review aims to provide a summary of developments on diagnostics, proteomics and translational advances including CFTR therapeutics. Recent directions on therapeutics are also discussed in order to present how the novel modulators may impact on life expectancy for almost all individuals with CF.

The F508del is the most prevalent CF-causing mutation. This mutation leads to CFTR protein misfolding that is arrested by the endoplasmatic reticulum (14). Nevertheless, a small fraction of the mutant protein may evade the quality control checkpoints and reach the membrane.

Other CFTR mutations may impair mRNA and protein expression, function, stability or a combination of these. The classification has historically been evolving according to the gained knowledge (14), and the current scheme is composed of six classes described above. Other systems have also been proposed to take into account the multiple possible variations of CFTR gene (15). However, the classification system in six different classes has been useful in understanding the distinct molecular defects of different CFTR mutations. Also, it became worldwide used to understand the development and effects of pharmacotherapies recently introduced for specific genetic variations.

Mutations in classes I-III are usually associated with a classical and more severe disease, while those in classes IV-VI are related to milder (or atypical) phenotypes. Individuals with CF may nevertheless carry different CFTR mutations on the two alleles, leading to thousands of possible combinations of CF genotypes. Noteworthy, clinical phenotypes and therapeutic responses may differ between individuals carrying the same CF genotypes (16, 17). In fact, several other factors influence disease severity beyond CFTR mutations: gene modifiers, social status, patient's lifestyle, respiratory infections and adherence to therapies (18).

Numerous libraries of compounds have been screened by distinct high-throughput screening (HTS) methods and using several cell models. These experimental approaches contributed to the identification of molecules from different chemical series (19–21).

CFTR modulators enhance or even restore the expression, function, and stability of a defective CFTR channel by distinct mechanisms. CFTR therapeutics have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers (22). To date, four CFTR-directed modulators have reached the market for the treatment of CF patients carrying specific CFTR mutations (23, 24).

Only after clarifying the pathophysiology and identifying the mutations that cause the disease, the arduous search for treatments that acted at the genetic level began (13). Up to the last decade, however, the treatments available for CF were intended only to control the consequence or complications of the disease (Figure 1). Then, in 2011, the publication of a study that demonstrated the effectiveness of the first CFTR modulator (25) started the Era of Modulators, which revolutionized the treatment of CF. The precursor to this series of modulators is Kalydeco® (Ivacaftor), a drug referred to as a CFTR “potentiator”, which was initially intended for use in the treatment of patients with the G551D mutation. Although this discovery was important, the profile of patients eligible for the use of this medication was still very restricted, so that, in subsequent years, the search for drugs that could cover more mutations and produce even more significant results was intensified (Table 1). In the following years, two new therapies were developed: Orkambi® (Ivacaftor/Lumacaftor) and Symdeko® (Tezacaftor/Ivacaftor) (25–27). Lumacaftor is a CFTR “corrector” and its association with Ivacaftor allowed the use of this therapy in homozygous F508del patients, representing a great advance due to the high prevalence of this mutation (28). Tezacaftor is also a CFTR “corrector”, and its combination in Symdeko® has achieved very satisfactory results in patients homozygous for F508del and heterozygous for residual function mutations (26). Even so, none of the modulators produced so far was sufficient to generate results in heterozygous patients with an F508del mutation. It was only 8 years after the production of the first CFTR modulator, that an effective and safe combination of CFTR potentiators and correctors was reached that could be used by patients with a single F508del mutation (23). This combination involves a triple therapy of Elexacaftor, Tezacaftor and Ivacaftor (Trifakta®), which has been approved by the US Food and Drug Administration for patients 12 years and older with at least one F508del mutation, which represents ~90% of the American population with Cystic Fibrosis (29). The results of phase 3 studies were an increase of 10% in FEV1, improved patient-reported quality of life, decrease in sweat chloride value, improvements in BMI, and reduction in the number of pulmonary exacerbations (23, 24, 29).

Although it is already possible to observe the great clinical impact of these drugs, there are still many economic, social, and clinical challenges to be faced to enable their large-scale use. One of the biggest obstacles is the cost of these medications, which are around €150–200,000 per patient per year, causing many countries to not fund the therapies through their health systems (30). Furthermore, it is important to remember that the therapeutic effects of CFTR modulators depend on the mutation and class to which they belong, which excludes a significant portion of the population with CF. Finally, there is a considerable risk that the use of CFTR modulators may cause drug-drug interactions in cytochrome P450 3A4 and various adverse effects (31). For these reasons, new compounds with different mechanisms of action are already in the clinical trial phases, one of them (32) already being in phase 3. In addition, therapies are currently being studied that aim to correct protein function through other pathways, such as those with mRNA and viral vectors. The mRNA therapy aims to restore the CFTR protein to adequate levels through a distribution of normally functioning encoded mRNA copies, regardless of the patient's mutation (30). Therapy with viral vectors consists of inserting complementary DNA with normal CFTR into plasmid DNA, aiming for a transfection in lung cells through viral vectors (30, 33).

The impact of these discoveries over the years is evident, achieving advances not only in the pulmonary function of patients, but also in its quality and life expectancy (Figure 1). However, several obstacles remain to be overcome for the development of new therapies, such as the inclusion of patients with rarer mutations, treatment costs, regulatory difficulties in carrying out large clinical trials, among others (13, 34–36).

The CF Foundation Registry was created in 1966 to track the health of people with cystic fibrosis who receive care at CF Foundation-accredited care centers and agree to share their data to inform continued quality improvement in treatment and specialized care. Each year, the CF Foundation analyzes these data and shares this information with the CF community through the Patient Registry Annual Data Report. Based on 2019 Registry data, the life expectancy of people with CF who are born between 2015 and 2019 is predicted to be 46 years. Data also show that of the babies who are born in 2019, half are predicted to live to be 48 years or older (37). The latest CF Foundation Patient Registry data show steady gains in survival for people with CF.

In conclusion, advances in diagnosis and treatment, as well as improvements and expansion in multidisciplinary care centers, have changed the situation for CF patients, resulting in a significant increase in life expectancy. Expanding the use of new drugs may result in improved mortality rates, life expectancy, and quality of life for CF patients.