Current treatment options for patients with cystic fibrosis include supportive treatment to improve breathing and lung function, as well as symptomatic treatment targeting the infections and pulmonary inflammation. Most of the currently available anti-inflammatory and immunomodulatory therapies fail to effectively resolve the dysregulated inflammation without drastically impairing the immune response [84 2001, chmiel, 1999, 97, 250-279]. Several elements of the disrupted inflammation and the dysregulated innate and adaptive immune
responses have been considered for development of new therapeutic targets.
i. CFTR based therapies
Novel therapeutic approaches aim at targeting CFTR function. As discussed earlier, CFTR mutations contribute to altered inflammation in several aspects [250-256]. Patients with cystic fibrosis have 2 mutated CFTR alleles which result in decreased number and malfunction of the CFTR channels. Genotype-directed therapies use genetic approaches to restore expression and function of CFTR channels. The personalized approaches have been successful in restoring epithelial and phagosomal functions; however, they are of limited usefulness in
advanced disease stages [250-253]. Additionally, small molecules have been developed as CFTR modulators. These modulators target specific CFTR variants and mutations that are associated with a minimum level of CFTR protein
expression. Therefore, these CFTR modulators potentiate and improve the function of CFTR expressed on cell surface level [250-253]. Ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor are FDA approved CFTR
potentiators. They improve ion flux across the channels, improve lung function, and reduce morbidity and mortality. However, the use of these CFTR modulators remains limited for patients with a particular mutation [254-256].
ii. Anti-inflammatory therapies
a. Corticosteroids
Corticosteroids are the main anti-inflammatory agents used in cystic fibrosis patients [81, 257]. They are widely available and efficiently dampen airway inflammation in a global and non-specific way. There are several oral, inhaled, and intravenous corticosteroid formulations that are extensively used in patients with cystic fibrosis [81, 256]. Corticosteroids are effective in slowing disease progression and suppressing excessive inflammation. However, long-term steroid use is associated with many adverse events including growth retardation and even decline in lung function [256-259]. Nonetheless, steroids are broadly used in cystic fibrosis as targeted anti-inflammatory drugs are not available.
b. Therapies targeting neutrophil recruitment
Multiple approaches aim to correct specific alterations of the immune response [8]. Clinicians and immunologists are attempting to target the signaling pathways involved in neutrophil recruitment. For instance, a human monoclonal antibody against IL-8 is proving to be promising in clinical trials [260]. Besides targeting IL- 8, studies in mice show that neutralizing IL-17 is also promising and it effectively
reduces neutrophil influx in response to PA [260-262]. However, targeting IL-17 with neutralizing antibodies is challenging due to the importance of this cytokine in the clearance of pathogens [8, 260-262].
Other therapies directed against neutrophils include the attempt to deliver or stimulate the endogenous release of anti-proteinases (α1-proteinase inhibitor) [105, 263-267]. Several studies are evaluating the potential to formulate
appropriate dosage forms or genetic approaches to achieve therapeutic levels of these proteinase inhibitors [105, 263-266]. A recent study just passed phase-II clinical trials where they show limited toxicity with an inhaled form of α-1
antitrypsin (a human anti-protease) [267].
Moreover, new therapies are directed to clear the pathogenic DNA released from dead neutrophils and bacteria [268, 269]. The release of DNA fragments results in increased mucus thickness and activation of several inflammatory cascades. Recombinant DNase was evaluated in several human trials where it proved to reduce mucus thickness, decrease neutrophil influx and recruitment, improve lung function, and decrease exacerbations [268, 269]. In fact, some DNases are FDA approved for use in cystic fibrosis.
c. Therapies against NF-κB signaling pathway
Several approaches target specific pathways involved in exaggerated
inflammation including that governed by NF-κB [84 2001, chmiel, 1999, 97, 257- 259, 270, 271, 279]. Recombinant IL-10 succeeds in regulating inflammation by inhibiting NF-κB activation in murine models of PA pneumonia. However, it has not yet been assessed in humans [280]. A phase-II clinical trial is currently evaluating the efficacy of Genestein which is a tyrosine kinase inhibitor that stimulates CFTR and inhibits NF-κB activation [270, 271]. Other therapies in development which target NF-κB activation in cystic fibrosis include (1) HE3286, which is currently in phase I/II clinical trials; (2) azithromycin, which passed a
phase III clinical trial and is suggested to inhibit NF-κB and AP1 activation; (3) curcumin, which is proven to block NF-κB activation and rescue mutated CFTR from degradation; (4) and ibuprofen and fenretinide/docosahexaenoic acid (in phase II clinical trial), which are shown to regulate NF-κB activation and lipid-raft formation and clustering [97].
A major concern for developing an NF-κB inhibitor is the threat to suppress immunity and pathogen clearance. Attempts are being made to target NF-κB activation locally in the lungs by developing dosage forms that deliver the inhibitors to the lungs directly. Alternative approaches include screening for specific molecular targets that would provide controlled inhibition of NF-κB without global inhibition. Therefore, optimizing currently available therapies by identifying specific pathways by which they exert their beneficial effects is essential to overcome the failure and adverse drug effects of the current therapies.
d. Cell-based therapies
Cellular therapy is also an interesting and promising venue for cystic fibrosis treatment [272-274]. Clinical studies show a significant reduction of bacterial replication and infectivity along with increased soluble bactericidal substances in the airways of cystic fibrosis patients treated with human mesenchymal stem cells. Other cellular therapies include the restoration and transfer of engineered epithelial cells, monocytes, or macrophages [272-274]. Some of these
approaches made it into clinical trials while others are still at the level of experimental animal models [272-274].
iii. Antimicrobial therapies
Scientists are developing new antimicrobial molecules and evolving better ways to deliver the currently available antibiotics [275-277]. New dosage forms deliver
high concentrations of antibiotics locally into the lungs which can allow the compounds to reach into the inaccessible areas of infection in the cystic fibrosis airways. Rapamycin and azithromycin can be successfully delivered in high concentrations packed in engineered nano-particles [275, 276]. Other therapies directed against the infecting microorganisms include the development of viral phages to kill the colonizing bacteria [277]. However, resolution of chronic infection is promising, no evidence is available on how helpful it would be because inflammation is dysregulated independent of the infection status.
In summary, cystic fibrosis pathology is based on the chronic infections and the non-resolving pulmonary inflammation. Our increased understanding of the different components of cystic fibrosis pathology and the specific alterations in the immune system and the lung microenvironment identifies novel therapeutic targets. In fact, many therapies in development are targeting these specific alterations including (1) therapies which restore CFTR function; (2) therapies which control neutrophil inflammation; (3) therapies which control NF-κB
activation; (4) therapies which restore functional immune cells; (5) and therapies which clear non-resolving infections. Additionally, the advancement in therapeutic options necessitates the consideration of combination therapy that would target infection, inflammation, genetic, and symptomatic components of this complex disease [84 2001, chmiel, 1999, 97, 250-278].