# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 3 Non-Gene Therapy for CF
### Targeting Bacterial Biofilms  
_P. aeruginosa_ infection is a well-established cause of morbidity in CF [121], although other pathogens have also been found in the CF lung that could induce biofilm formation. Lung function failure in CF has also been associated with Methicillin-resistant _Staphylococcus aureus_ (MRSA) [122]. In addition, _Haemophilus influenzae_ frequently colonizes the CF lungs [123], and _Aspergillus fumigatus_ has been isolated from sputum of CF patients [124]. CF patients show high levels of _Burkholderia spp_ in the salivary fluid [125]. _Streptococcus pneumoniae_, and _Klebsiella pneumoniae_ have also been found \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Name** & **Therapeutic Approach** & **Target CFIR Mutations** & **Development Stage** & **Ref** \\ \hline \hline \multicolumn{2}{c}{lavcinder} & Pertentiator & Class III (G51D mutation) & FDA-Approved, 2012 & [107] \\ \hline \multicolumn{2}{c}{N9115 (Cavosentral)} & Stabilizer & Class II (P508 del homozygous) & Phase II(Discontinued) & [109] \\ \hline \multicolumn{2}{c}{Orkambik® (lumcalororor + ivacaftor)} & Corrector + potentiator & Class II (P508 del homozygous) & FDA-Approved, 2015 & [112] \\ \hline \multicolumn{2}{c}{Symdeck®(tereztohr + ivacaftor)} & Corrector + potentiator & Class II (P508 del homozygous) & FDA-Approved, 2018 & [112] \\ \hline \multicolumn{2}{c}{Trikafafn\({}^{\text{m}}\)(ivacaftor + texacaftor)} & Pertentiator + corrector + corrector & Class II (P508 del heterozygous) & FDA-Approved, 2019 & [113] \\ \hline \multicolumn{2}{c}{PT1-801/PT1-808/PT1-428} & Corrector + potentiator + amplifier & Class II (P508 del homozygous) & Phase II & [108;114] \\ \hline \multicolumn{2}{c}{PTC124 (Ataluren)} & Read-through & Class I (PTC mutation) & Phase II(Discontinued) & [114] \\ \hline \multicolumn{2}{c}{Duramycin} & Cl\({}^{+}\) stimulator through CaCCs & - & Phase II(Discontinued) & [111] \\ \hline \multicolumn{2}{c}{Denthosol} & Cl\({}^{+}\) stimulator through CaCCs & - & Phase II(Discontinued) & [111] \\ \hline \multicolumn{2}{c}{SPX-101} & ENaC inhibitor & - & Phase II & [120] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Cystic fibrosis (CF) small molecule therapies and their targeted mutations. in CF patients' sputum [125]. _P. aeruginosa_ chronic infection is prevalent in about 80% of adult CF patients [126]. Biofilms have been identified in the CF lung. Biofilm growth in CF is associated with several mutations, adaptation of the bacteria to the lung conditions and resistance to antibiotics [126]. _P. aeruginosa_ CF isolates display altered expression of virulence factors which affects motility, antimicrobial resistance, lipopolysaccharide, and production of some secreted products such as pyocyanin [127]. _P. aeruginosa_ pyocyanin might inhibit the function of antioxidants and block Cl\({}^{-}\) transport in human bronchial epithelial cells [128]. _P. aeruginosa_ can also adopt a mucoid phenotype in the CF lung [129]. Once _P. aeruginosa_ becomes mucoid and forms biofilm, the eradication of infection is greatly difficult. This leads to immune response disturbance, impaired pulmonary function, and persistence of chronic disease [129]. Antimicrobial peptides (AMPs), which consist of 12 to 50 amino acid residues, are active agents with antimicrobial and antibiofilm activities [130]. They play an essential role in innate immunity in humans as well as other species [131]. For instance, magainins are standard natural AMPs found in the African frog _Xenopus laevis_. Cathelicidins and defensins are important AMPs isolated from human leukocytes, which disrupt the microbial cell wall, and consequently, contribute to innate immune defense [132]. Several studies have shown that AMPs display bactericidal effects, modulate inflammatory responses, and prevent biofilm formation [133; 134]. The innate defense regulator-1018 (IDR-1018) peptide is considered to be a promising antimicrobial agent, owing to its effectiveness against _P. aeruginosa_.