Rafeeq and Murad J Transl Med (2017) 15:84

DOI 10.1186/s12967-017-1193-9 Journal of

Translational Medicine

REVIEW Open Access

Cystic fibrosis: current therapeutic

targets and future approaches
Misbahuddin M. Rafeeq1*  and Hussam Aly Sayed Murad1,2

Abstract 
Objectives:  Study of currently approved drugs and exploration of future clinical development pipeline therapeutics
for cystic fibrosis, and possible limitations in their use.
Methods:  Extensive literature search using individual and a combination of key words related to cystic fibrosis
therapeutics.
Key findings:  Cystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormal-
ity of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but
eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy,
extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and
complication prevention but recently the protein rectifiers are being studied which are claimed to correct underly-
ing structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising
approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.
Conclusions:  The treatment has a long way to go as most of the existing therapeutics is for older children. Other
limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches
like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.
Keywords:  Chloride, Sweat, Respiratory, Hereditary, CFTR

Introduction and pathophysiology The CFTR protein lets chloride to pass through the
Cystic fibrosis (henceforth CF) is autosomal recessive mucus producing cells after which the water follows
disease involving mucus and sweat producing cells affect- and mucus becomes thin. However, defective CFTR
ing multiple organs with lungs most severely affected results in thick and sticky mucus obstructing the path-
leading to death in 90% of patients [1]. A mutation in ways [7], leading to serious lung infections especially
Cystic fibrosis trans-membrane conductance regulator pseudomonas. There is massive neutrophil infiltration
(henceforth CFTR) gene changes a protein (a regulated releasing elastase, which overpowers the lung antipro-
chloride channel), which regulate the activity of other teases contributing to tissue destruction [8]. Addition-
chloride and sodium channels at the cell surface epithe- ally, degranulating neutrophils release large quantities of
lium [2–4]. There are about 70,000 worldwide cases and nucleic acids and cytosol matrix proteins contributing to
approximately 1000 new cases are added each year. CF is the mucus hyper-viscosity [9].
most common in white people of north European ances- In the GIT, the mucous plugs obstruct the canaliculi of
try having 1 in 2000–3000 births [5] and least in Asian- pancreas and gall bladder duct preventing enzyme and
Americans having 1:30,000 newborns [6]. bile flow into duodenum triggering malabsorption and
digestion abnormalities. Additionally, Distal Intestinal
Obstruction Syndrome (DIOS), which is distinctive to
CF, may occur especially in those with pancreatic insuf-
*Correspondence: [email protected]
1
Department of Pharmacology, Faculty of Medicine, King Abdulaziz ficiency. This is characterized by ileo-cecal obstruction
University, Rabigh Campus, Jeddah 21589, Saudi Arabia of inspissated intestinal contents [10, 11]. There is also
Full list of author information is available at the end of the article

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provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
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Rafeeq and Murad J Transl Med (2017) 15:84 Page 2 of 9

imbalance of minerals in blood due to loss of extra salt in Complications

sweat leading to dehydration, arrhythmias, fatigue, weak- Respiratory system complications include Bronchiecta-
ness, heat stroke and rarely death. sis, Chronic infections leading to pneumonia, growths
(nasal polyps), hemoptysis, pneumothorax and eventu-
Genetics ally respiratory failure.
The CFTR gene is located at 7q31.2. More than 1900 Digestive system complications include nutritional
mutation have been identified of which ‘F508del’ (dele- deficiencies including fat and fat soluble vitamins and
tion of three bases coding for phenylalanine at the 508th diabetes (Nearly 20% of people with cystic fibrosis
position) is the most common [12]. Six classes of muta- develop diabetes by age 30). Additionally, progressive
tions are described as depicted in Table 1. hepatic dysfunction, gallstones, intestinal obstruction,
Class I mutations contribute to protein production intussusception, small intestine bacterial overgrowth
defect leading to complete absence of CFTR protein, (SIBO) and distal intestinal obstruction syndrome
found in 2–5% cases worldwide with the exception of (DIOS) may also manifest.
Ashkenazi Jews, in whom 60% of patients carry at least Other complications may include Infertility, Osteopo-
one copy. Class II mutations contribute to protein pro- rosis, Electrolyte imbalances and dehydration manifest-
cessing abnormality leading to aberrant localization. ing as increased heart rate, fatigue, weakness and low
It includes F508del which is the most common muta- blood pressure.
tion accounting for 70% of the disease-causing alleles in Because of better quality medical interventions and
US. Approximately 50% of the CF patients are homozy- comprehensive care, there is a remarkable increase in
gous and 90% are heterozygous for this allele. Class III percentage of patients (29.2% in 1986 to 49.7% in 2013)
mutations contribute to protein regulation abnormali- surviving above the age of 18 years.
ties leading to a decreased activity. It also includes other
mutations especially in regulatory domain. G551D is Treatment
most common class III mutation. Class IV mutations The goals of treatment primarily include:
contribute to protein conduction abnormalities leading
to altered frequency of ion flow. Most common mutation Respiratory system
is R117H. Class V mutations lead to a reduced amount Preventing and controlling lung infections—antibiotics
of functional CFTR protein [13–17] and class VI muta- are prescribed. These mainly consist of inhaled forms
tion cause an enhanced protein turnover. Patients carry- of azithromycin, tobramycin, aztreonam and levofloxa-
ing Class I–III mutations manifest a more severe form of cin. Other antibiotics recommended are ciprofloxacin,
disease. cephalexin, amoxicillin and doxycycline depending on
However, possible influences of gene modifiers for the sensitivity patterns [19, 20].
example TGF-beta1 and mannose-binding lectin have Control of airway inflammation—NSAIDs, inhaled and
downplayed the clinical significance of a specific combi- systemic steroids and cromolyn [21].
nation of mutations [18].

Table 1  Depicting various classes of mutations, the primary defect and the outcome with examples
Mutation class Defect Outcome Common mutations

I Protein production Complete absence of CFTR protein due to premature G542X, W1282X, R553X, 621+G>T
mRNA termination (nonsense or frame shift mutation)
[18, 21, 22]
II Protein processing Inability of protein to localize to correct cellular location F508del, N1303K, A455E
due to abnormal post-translational modifications [18]
III Protein regulation Decreased activity of protein (chloride channel) in G551D
response to ATP due to abnormalities of the nuclear
binding fold regions [18]
IV Protein conduction Frequency of flow of ions and channel opening duration R117H
are reduced though there is generation of chloride cur-
rents on stimulation with cAMP [18]
V Reduced amount of functional CFTR Stability of mRNA and/or mature protein is compromised A455E
[19, 20]
VI Normal amount of functional CFTR Enhanced turnover due to C-terminus abnormalities Q1412X
Rafeeq and Murad J Transl Med (2017) 15:84 Page 3 of 9

Reducing viscoelasticity and removing thick, sticky

mucus from the lungs and dilating the airways—inhaled
β agonists with humidified oxygen; a 3–6% hypertonic
saline solution and dornase alfa are recommended
[22–24].
Additionally exercise and physiotherapy including pos-
itive expiratory pressure (PEP) device or a high frequency
chest wall oscillation device (a percussion vest) is recom-
mended [25].

GIT
Preventing or treating intestinal blockages—oral rehy-
dration and osmotic laxatives (incomplete blockage) and
hyperosmolar contrast enemas (complete DIOS). A bal-
anced electrolyte intestinal lavage solution or enema con-
taining (diatrizoate meglumine and diatrizoate sodium)
depending on vomiting status [26]. To prevent recur-
rence, regular administration of oral polyethylene glycol
3350 may be given for 6 months to 1 year. Fig. 1  The main pathophysiological dysfunctions and treatment
Pancreatic insufficiency—pancreatic enzyme replace- modalities for CF patients. Inner trapezoid boxes depict the patho-
physiological abnormalities and outer rectangular boxes depict the
ment therapy (PERT) containing multiple combinations
main treatments. The texts connecting the outer boxes show non-
of proteases, lipases and amylases [27]. pharmacological management

Nutrition and electrolyte
Providing appropriate nutrition and preventing dehy-
dration—a high-calorie-fat diet, supplemental vitamins first successful medicine to rectify the defective protein
ADEK, and minerals including fluoride and zinc are rec- and has proven to be very effective in two large multi-
ommended. Additionally sodium chloride supplementa- centric trials, STRIVE and ENVISION [30, 31]. Marked
tion is given tailored to patient’s age and environmental improvement in ­FEV1, body weight and quality of life
conditions [28]. were observed. Now FDA has expanded its use in other
Figure 1 summarizes the main abnormalities and treat- mutations and also children aged 2–5  years based on
ment approaches in CF patients. the results of KIWI trial [32]. Additionally, a phase IV
In the recent past, Denufosol, an agonist of P2Y2 recep- study (GOAL) also reported improvements in F ­ EV1 and
tors was tried in CF patients but it eventually failed after FVC, BMI, quality of life and decreased sweat chloride
early promising results. The detailed analysis is beyond concentration in patients carrying at least one G551D
the scope of this review. allele. More than 72% patients in this trial also car-
ried F508del as second allele [33]. The G551D mutation
Current and future medicinal products causes the channel to act like a locked gate, preventing
The current and future therapeutic targets are mainly the trans-conductance of chloride and fluid. The location
focused on correcting structural and functional abnor- of channel is proper but the function is impaired. Iva-
malities of CFTR protein. Additionally, some agents for caftor increases the time of channel in open state. But the
symptomatic improvement are also in pipeline. main limitation of this therapy is that G551D mutation
is present in only 2.3% patients [34]. It is not found to be
CFTR modulators effective in the most common F508del (class II) mutation
A new group of drugs called CFTR modulators are avail- because of decreased availability of protein. Addition-
able which are able to correct the basic defect in CF, i.e. ally, the high cost of therapy may also be a limiting factor
CFTR protein itself though the exact mechanism is not (ICER: £335,000–£1,274,000/QALYs gained [35].
fully elucidated.
Lumacaftor
Ivacaftor Another CFTR modulator, lumacaftor has shown favora-
Developed by vertex pharmaceuticals and approved by ble results in F508del mutation. This is the most common
FDA in 2012 for children  ≥6  years having rare muta- mutation affecting approximately 1/3rd CF population in
tion, G551D (class III), ivacaftor (Kalydeco) [29] was the US and nearly 70% in EU. This mutation affects the heat
Rafeeq and Murad J Transl Med (2017) 15:84 Page 4 of 9

stability due to misfolding of NBD1 domain and restricts which include (a) non-significant response in F508del
the CFTR in ER for subsequent degradation. It fails to mutation heterozygotes by ivacaftor; (b) need to continue
localize to correct epithelial location and achieve normal other daily symptomatic treatment; (c) interaction with
structure. Increased transport of protein to cell surface CYP3A inducers and inhibitors; (d) side effects including
was observed in  vitro using cultured human bronchial elevated transaminases, cataract, oropharyngeal pain and
epithelium [36]. Nevertheless, despite increased trans- URTI; (e) negligible benefit in <12 years old; (f ) need of
port of protein to proper location, no correction of the higher dose up to 600 mg (in case of lumacaftor); and (g)
underlying functional impairment was observed. Moreo- mutual interaction of lumacaftor and ivacaftor leading to
ver, another in  vitro study revealed contrasting negative increased metabolism of ivacaftor and need of a higher
results [37] which were further reinforced by a clinical dose combination.
trial. No significant improvement was observed in F ­ EV1, Additionally, because of the multi domain structure
CFQR scores and respiratory exacerbation rates [38]. and sequential folding of CFTR, no single “corrector
drug” can fix all the misfolding in different domains, so a
Orkambi combination of drugs is a must. Moreover, from a clinical
Based on the individual mechanisms, a combination of trial perspective, there are sample size issues as specific
lumacaftor and ivacaftor (Orkambi) was proposed to cor- criteria (primary and secondary endpoints) make selec-
rect both, including protein trafficking as well as channel tion more difficult in already narrowed mutation specific
gating abnormalities. population warranting unique adaptive trial designs.
Initially, phase II trials were conducted for
both homozygous and heterozygous F508del Corrector/modifier therapeutic agents in clinical
patients  >12  years old but only homozygous patients development pipeline
showed clinically significant results. Two large phase III Many other compounds depicting corrector/potentiator
trials, TRAFFIC and TRANSPORT were conducted with activity besides read-through and gene transfer agents
the combination therapy (600 + 250 and 400 + 250 mg and are undergoing various phases of studies as men-
versus placebo) in patients  ≥12  years with primary tioned below.
endpoint as F ­EV1 improvement at 24  weeks. Patients
completing the study were progressed to 48  weeks ••  4PBA (sodium 4-phenylbutarate): though the mecha-
PROGRESS trial. The isolated as well as pooled results nism of action is not certain but this compound has
showed a significant improvement in parameters includ- shown to enhance chloride transport in vitro and in
ing ­FEV1, reduction of exacerbations, decrease in hospi- patients having F508del [43].
talizations, increase in BMI and CFQR scores; consistent ••  VRT-532: preclinical studies confirmed that this
across different dosage regimens and patient groups. The compound corrects the CFTR structural abnormality
adverse effects were comparable to placebo group except and increases the protein expression and stability in
one case of death during extension phase [39, 40]. patients carrying F508del and G551D mutations but
Additionally, a phase I study in homozygous chil- showing more affinity for F08del [44, 45].
dren ≤12 years also showed promising results but further ••  N6022: increases quantity of CFTR at the epithelium
advance phase studies are needed [41]. However, when and decrease inflammation. This compound inhib-
compared to ivacaftor monotherapy in patients hav- its S-nitrosoglutathione reductase which cause the
ing G551D mutation in a separate study, there was sig- breakdown of S-nitrosoglutathione, as a result, levels
nificantly less improvement in pulmonary function with of S-nitrosoglutathione increase which functions as a
combination therapy [42]. signaling molecule for protein production [46]. They
Orkambi (lumacaftor + ivacaftor) is approved recently also limit the binding of HOP (Hsp70/Hsp90 organ-
for homozygous F508del patients  ≥12  years. Orkambi izing protein) to mature form of CFTR, eventually
acts by a two-step method. Lumacaftor assists in moving preventing its degradation. Currently this is in phase
the defective protein to its correct location and ivacaftor 1/2 trials in F508del homozygotes [47].
rectifies and enhances its activity eventually increas- ••  Ataluren (PTC124): it promotes the read-through
ing the conductance of ions and fluid. Figure  2 shows of non-sense codons in the mRNA of CFTR (Fig. 1).
the possible mechanism of action of Orkambi and other After promising results in phase II, a phase 3 trial
drugs. in 2011 also showed a lower rate of decline in lung
function. However, another phase 3 trial showed
Possible limitations non-significant results (­FEV1 similar in placebo and
Though the arrival of CFTR modulators have improved drug group) and increased creatinine which was later
the CF management but there are still some limitation attributed to inhaled tobramycin [48]. Other trials
Rafeeq and Murad J Transl Med (2017) 15:84 Page 5 of 9

Fig. 2  Depicting the action of Orkambi (lumacaftor + ivacaftor) and other agents in cystic fibrosis. Orkambi is a combination of two drugs which
acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies the gate opening time
and enhances its activity eventually increasing the conductance of chloride ions followed by water. Read through agents for example Ataluren
increase read through of Premature Termination codon enhancing production of immature protein. Possible “Corrector” drugs act on post transla-
tional modifications to increasing stability and reducing degradation by binding to various domains of CFTR. p-TM post translational modifications,
GB golgi bodies, ER endoplasmic reticulum

are currently going on. Additionally a synthetic ami- ••  N91115(Cavosonstat): it increases levels of S-nitroso-
noglycoside NB124 has also depicted a restoration of glutathione which is decreased in CF patients. It has
CFTR activity up to 7% based on the same mecha- shown to increase the CFTR protein quantity. Just
nism of increased PTC suppression [49]. completed phase 1b trial with demonstrated safety
••  Tezacaftor (VX-661) in combination with ivacaftor: and undergoing phase 2a [53].
a phase 2 trial showed promising results and now ••  QR-010: it is an antisense oligonucleotide intended
this combination is being tried in phase 3. VX-661 to rectify the defective CFTR mRNA. It is given by
is expected to move the defective protein to correct inhalational route and under phase 1b at present [54].
location [50]. ••  Triple therapy of GLPG2665 (corrector) with
••  Riociguat: though originally approved for treatment GLPG2222 (another corrector) and GLPG1837
of pulmonary hypertension due to its synergistic (potentiator) has shown promising results in early
effect with nitric oxide and stimulation of guanylate preclinical studies depicting a sixfold more efficacy
cyclase [51], it is currently in phase 2 and preclinical than Orkambi while early phase human trials are still
studies have shown positive results regarding expres- going on [55–57].
sion of CFTR. ••  CTP656: it is deuterated ivacaftor which in a phase
••  QBW251: anticipated as a facilitator/potentiator I trial showed a reduced rate of clearance, increased
for channel dynamics, its mechanism is similar to half-life, significantly improved exposure and better
ivacaftor i.e. increasing the channel opening and plasma levels [58]. Other corrector drug candidates
is expected not to affect the membrane stability of are FDL160, FDL169 (phase I), FDL392 and FDL304
CFTR as by lumacaftor. It is currently undergoing are also in early developmental pipeline [59].
phase 2 [52].
Rafeeq and Murad J Transl Med (2017) 15:84 Page 6 of 9

••  PGM169/GL67A (plasmid + cationic liposome): is a proteostatis modulation may shift the interactome to a
non-viral CFTR gene transfer agent. It is in phase IIb more healthy state thus normalizing the CFTR [67]. As
trial. Repeated nebulization in patients ≥12 years of a matter of fact, a deficiency in autophagy pathways as
age showed a modest but significant improvement in evidenced by reduced autophagosome formation, and
lung function but the response is highly varied even the buildup of sequestrosome 1 was discovered in CF air-
­FEV1 deteriorating in some patients [60]. Addition- way cells. Myriad proteostasis network interactions have
ally, the placebo group received saline based instead been identified but no human study is done yet. Detailed
of saline based nebulization. Moreover, secondary discussion on these proteostasis networks is beyond the
outcomes like CFTR expression levels, inflammatory scope of this review.
markers and NPD showed non-significant results. Another approach is exploration of role of chemi-
Another gene transfer agents, Ad5-CB-CFTR, cal and pharmacological chaperones. They do not
H5.001CBCFTR (with adenovirus) are in phase 1. act directly on CFTR but on smaller cellular proteins
••  PTI428: is projected as a ‘CFTR amplifier’ drug can- increasing their stability thus modifying the CFTR inter-
didate currently in phase I has shown promising actome. Some examples include curcumin and thapsigar-
results in preclinical studies on HBE cells. Addition- gin (reducing ER calcium and increasing F508del-CFTR
ally, the PTI-NC-733 is a combination of PTI428 release), Bortezomib (preventing ER associated degrada-
with a corrector and potentiator and has revealed tion of F508del-CFTR by increasing HsP70) and Miglus-
better outcomes in  vitro than a combination of iva- tat (inhibitor of α-1,2-glucosidase eventually reducing
caftor and lumacaftor [61, 62]. cytoplasmic degradation of CFTR). Some other com-
••  Duramycin (Moli1901/Lancovutide): activates CaCC pounds include VRT-325, VRT-532 and Corr-4a reduc-
in airway epithelium. Has shown improved F ­ EV1 in a ing ubiquitination susceptibility of CFTR. But for most
phase II trial. compounds, no corrector activity in humans is yet
••  PDE5 inhibitors: a study on F508del murine model established. Moreover, there are technical difficulties in
of CF showed an increased chloride transport in res- bringing these agents to clinical trials and a significant
piratory mucosa on inhalation of PDE5 inhibitors improvement is not anticipated.
[63]. Also a decrease in sputum neutrophil elastase Another promising approach is gene editing with the
was found in a clinical study [64]. So, a phase II trial help of nucleases like zinc finger nucleases, transcription
[NCT01132482] is underway to test for the NPD, activator-like effector nuclease and especially CRISPR/
sweat sodium and chloride concentration, spiromet- Cas9 (clustered regularly interspaced short palindro-
ric parameters and lung clearance index. Addition- mic repeats associated with Cas9 nuclease). Engineered
ally, the PDE5 inhibitors are also being tested for nucleases cut the mutant DNA precisely and then wild
increased exercise tolerance [NCT02057458]. type DNA is recombined to produce a normal transcript.
There is one proof of concept study in intestinal stem cell
Cysteamine: by inhibiting transglutaminase 2 organoids of CF patients carrying two F508del mutations
(an important multifunctional intermediary in cell with CRISPR/Cas9 methodology [68].
autophagy), increases the expression of CFTR and In addition, there are many other compounds identi-
restores its function and decrease inflammatory media- fied through HTS that may bind and regulate different
tors in murine CF models and epithelial cell lines [65]. domains of CFTR and regulate channel activity but these
A phase II study is done in homo and heterozygous for are still in animal experimentation phase.
F508del CF patients in combination with epigallocate-
chin gallate (which inhibits overactive pleiotropic protein Newer therapeutic agents for symptomatic improvement
kinase eventually increasing stability of F508del CFTR). CF management not only requires CFTR correction and
The results reported a decrease in sweat chloride concen- modification but intensive symptomatic treatment tar-
trations, increased CFTR function, repair of autophagy, geting inflammation, infection, bronchial hydration and
decrease in inflammatory cytokines, and improvement in nutrition. Newer drugs targeting these issues are summa-
­FEV1 [66]. rized below briefly.
Other possible strategy is proteostasis modulation.
Growing evidence suggests that CFTR do not works as an Inflammation
isolated ion channel but is a component of wider cellular Andecaliximab, which is an antibody to Matrix metal-
signaling environment. The functional state of CFTR is loproteinase 9 (MMP9) is undergoing phase IIb and
modulated by the cellular environment and heterogeneity expected to reduce inflammation and improve lung func-
in cellular signaling. Differences in cellular protein inter- tion. However, the baseline FEV1 required for this drug
actomes were found between wild and mutant CFTR, so
Rafeeq and Murad J Transl Med (2017) 15:84 Page 7 of 9

is between 40 and 80% limiting its use in very severe CF Oral Glutathione is being tried in phase II as this anti-
[69]. oxidant is important for normal lung and GIT function.
Another compound in phase 1 is POL6014 which CF patients have depicted lower glutathione levels and
is synthesized to block neutrophil elastase function, oral glutathione is anticipated to improve growth and
eventually reducing the tissue destruction and lung decrease gut inflammation [74].
inflammation. Other agents like enzyme burlulipase for pancreatic
LAU-7b is a fenretinide, a member of retinoid com- insufficiency, lubiprostone for constipation and roscovi-
pounds related to vitamin A. Phase 2 study is yet to begin tine for pulmonary infection are currently being tested at
and it is expected to reduce the inflammatory response in various centers.
CF lungs.
CTX-4430 decreases the production of leukotriene B4, Conclusion
an inflammatory mediator elevated in CF. It is presently Though there is an improvement in management of CF
undergoing a phase 2 trial [70]. patients after the approval of CFTR modulators but it
Other anti-inflammatory compounds in clinical devel- is still falling short of mark because in CF, management
opment pipeline are α-1 anti-trypsin, CTX-4430, Elastase needs not only the protein rectifiers but also sympto-
Inhibitor AZD9668, JBT-101 (phase 2) for reducing matic treatment and intensive physiotherapy which
inflammation. require concomitant therapies. Myriad genotypes also
pose a challenge. Most of the ‘corrector’ drugs in the
Hydration and mucus clearance pipeline are for older children either >12 or 6–12 years of
AZD5634 is undergoing phase 1b study. It is anticipated age. Additionally most of these drugs are having serious
to block the sodium channel in CF airway, thus rehydrat- hepatic and other side effects in addition to high costs.
ing and thinning the mucus in the lungs, making it easier Moreover, many drugs discussed above are still in early
to clear. clinical phase with limited data and a confirmed benefi-
SPX-101 is another compound designed to block cial outcome cannot be guaranteed. There is also a need
sodium channel function in the lungs, currently undergo- to address the psychological and social burden of disease.
ing phase II study.
OrPro (ORP-100) is a modified form of thioredoxin, Future research
expected to decrease mucus viscosity in the lungs and Gene engineering techniques and new molecular targets
improve clearance from the CF airway. may be explored besides CFTR. Help of modern biology
OligoG (Alginate Oligosaccharide) has shown to approaches like DNA nanotechnology, systems biology,
decrease mucus thickness in CF airway. It is currently metabolomics, disease modeling and intracellular protein
being tested in phase IIb in Europe and UK. It can be kinetics may help to unravel new pathways and networks
used either as a dry powder or liquid for nebulization associated with cystic fibrosis and eventually new thera-
[71]. peutic targets. Additionally, the focus should also not
Other agents for rehydration of airway secretions be minimized on novel physiotherapy techniques, new
include bronchitol currently in phase 3 in US and drugs for symptomatic improvement and complications
already approved in UK, Australia and Russia (for prevention.
patients  >18  years); VX-371 (P1037) presently in phase
Authors’ contributions
II for blocking sodium channel and prolonging the dura- MMR conceived the idea, MMR and HASM searched the literature, MMR
tion of hypertonic saline stay [72]; GSK2225745 acting by drafted the manuscript with help of HASM. HASM draw the figure and cor-
silencing ENaC through RNA interference are underway rected the references. All authors read and approved the final manuscript.
to reach the patients. Author details
1
 Department of Pharmacology, Faculty of Medicine, King Abdulaziz University,
Nutrition Rabigh Campus, Jeddah 21589, Saudi Arabia. 2 Department of Pharmacology,
Faculty of Medicine, Ain Shams University, Cairo 11562, Egypt.
Liprotamase (Anthera AN-EPI3332) is a pancreatic
enzyme replacement for CF-related pancreatic insuffi- Acknowledgements
ciency undergoing phase 3 study [73]. None.
AquADEKs-2 undergoing phase II is a balanced com- Competing interests
bination of fat-soluble vitamins and several antioxidants The authors declare that they have no competing interests.
including beta-carotene, mixed tocopherols, coenzyme
Consent for publication
Q10, mixed carotenoids, and minerals like zinc and All the authors have read and approved the final version of manuscript and
selenium. give consent.
Rafeeq and Murad J Transl Med (2017) 15:84 Page 8 of 9

Funding 22. Salvatore D, d’Andria M. Effects of salmeterol on arterial oxyhemo-

No source of funding was obtained for this work. globin saturations in patients with cystic fibrosis. Pediatr Pulmonol.
2002;34:11–5.
23. Robinson M, Regnis JA, Bailey DL, et al. Effect of hypertonic saline,
Publisher’s Note amiloride, and cough on mucociliary clearance in patients with cystic
Springer Nature remains neutral with regard to jurisdictional claims in pub- fibrosis. Am J Respir Crit Care Med. 1996;153:1503–9.
lished maps and institutional affiliations. 24. Quan JM, Tiddens HA, Sy JP, et al. A two-year randomized, placebo-con-
trolled trial of dornase alfa in young patients with cystic fibrosis with mild
Received: 1 February 2017 Accepted: 23 April 2017 lung function abnormalities. J Pediatr. 2001;139:813–20.
25. McIlwaine MP, Alarie N, Davidson GF, et al. Long-term multicentre
randomised controlled study of high frequency chest wall oscilla-
tion versus positive expiratory pressure mask in cystic fibrosis. Thorax.
2013;68:746–51.
26. Colombo C, Ellemunter H, Houwen R, et al. Guidelines for the diagnosis
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