# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 3 Non-Gene Therapy for CF  
### Small Molecules  
Although the conventional therapy currently in use for CF is primarily based on controlling disease symptoms without treating the underlying cause, this approach might reduce disease progression and enhance the patient's quality of life [103]. The recent discovery of CFTR modulators has provided a breakthrough in CF treatment, since they can be used to improve or potentially correct the CFTR function and other related complications [104]. Rapid developments in the field of drug discovery,owing to high-throughput screening technologies, have led to the screening of the activity of thousands of small molecules simultaneously, in a very short span of time, thus, aiding the identification of molecules that enhance the function of defective CFTR proteins [105]. Several small molecules that control CFTR malfunction are currently used in the clinical field and many are under investigation. Targeting CFTR mRNA or protein via modulators is one of the potential strategies for improving CF therapy by correcting gene malfunction, as shown in Figure 3. Typically, there are four main types of modulators--potentiator, stabilizer, corrector, and amplifier. The potentiator modulator targets the CFTR protein on cell membranes, causing the opening of CFTR ion channels and improving CFTR function [106]. VX-770 (Ivacaftor) is a commonly used potentiator in CF patients. It is the first FDA-approved CFTR potentiator drug and is used especially in cases of G551D class III mutation, which produces a defect in CFTR channel gating. It helps increase the movement of ions across the cell membrane and improves the opening of such defective channels [107]. Several potentiators like QBW251 and PTI-808 are in the process of undergoing clinical trials [108]. Stabilizers, like N91115 (Cavosonstat), are another class of modulators that have been investigated to improve CFTR protein stability. They act by reducing protein degradation in the endoplasmic reticulum (ER) and increasing protein residence time on the cell membrane [109]. The third type of CFTR small molecule modulator is the corrector. This modulator can correct the shape of misfolded CFTR protein, thereby restoring it to its original three-dimensional shape. Thus, it facilitates the functioning of the CFTR protein through its movement toward the cell surface [110]. VX-809 (Lumacaftor) is a corrector used to rectify the F508 del mutation, the most common type of CF mutation. This helps avoid the ER-mediated degradation of the CFTR protein by enhancing the interaction between the NBD1, MSD1, and MSD2 domains [111]. Corrector modulators are usually used in combination with potentiator modulators in CF treatment. Examples of this combination include the FDA-approved Orkambi(r) (lumacaftor combined with ivacaftor) and Symdeko(tm) (tezacaftor combined with ivacaftor) [112]. Post treatment with Orkambi(r), a significant in vitro effect has been reported on the transport of Cl\({}^{-}\) ions, compared to treatment with lumacaftor alone [112]. In the United States, a triple combination of ivacaftor, texacaftor, and texacaftor (Trikafta(tm)) has been recently approved for the treatment of CF patients aged 12 years and older carrying at least one F508 del mutation [112]. Clinical trial results have demonstrated that this combination increases the CF progression marker, i.e., the predicted percentage of forced expiratory volume in one second (ppFEV1) [113]. The fourth type of modulator is the amplifier. PTI-428, an amplifier, enhances the amount of CFTR mRNA and protein loaded on to the ER. The amplifier is usually combined with a corrector or potentiator modulator [114]. Figure 3: Different classes of CFTR mutations along with the possible therapeutic approach for each class. These modulators play a significant role in the treatment of most classes of CFTR mutations except class I, owing to a premature termination codon (PTC) mutation that leads to defective protein production [115].