Cystic fibrosis treatment; small molecule modulators vs genetic therapy

Salma Aly Elmallah, Raafat Soliman


Cystic fibrosis, CF, is one of the most common life-shortening genetic diseases among Caucasian population. It is a recessive genetic disease that is mainly caused by different types of mutations affecting the gene encoding for the cystic fibrosis transmembrane conductance regulator, CFTR, protein. CFTR is a multifunctional protein found in multiple organs in the human body, acting mainly as a trans-epithelial channel which regulates the flow of chloride and bicarbonate ions across epithelial membranes leading to the formation of a thin slippery mucous layer. A malfunctioning CFTR protein would lead to the accumulation of a thick viscous mucous layer blocking pancreatic ducts, intestines and airways which is the primary reason of death. Treatment of cystic fibrosis was mainly addressing the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Since the early 2010’s, the development of an actual therapy has reached great milestones including small molecule modulators and genetic therapy. Small molecule therapy depends on the development of small pharmacological agents that can bind to the mutated CFTR protein restoring its function. Pharmacological agents can act through different mechanisms and be mainly classified to; correctors and potentiators. On the other hand, gene-editing techniques are evolving showing very promising results. Gene therapy entails the relocation of a proper copy of the CFTR gene in the aim of expressing a functional CFTR protein. In this review article, small molecule and genetic therapies will be discussed including their development, benefits and limitations.


Cystic fibrosis, molecule modulators, genetic therapy

Full Text:



Lopes-Pacheco, M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front. Pharmacol. 2020, 10, 1662.

Simmonds, N.J. Cystic fibrosis and survival beyond 40 years. Ann. Respir. Med. 2011, 2 (1), 55-63.

Kessler, W.R.; Andersen, D.H. Heat prostration in fibrocystic disease of the pancreas and other conditions. Pediatrics. 1951, 8, 648-656.

Quinton, P.M. Chloride impermeability in cystic fibrosis. Nature. 1983, 301, 421-422.

Riordan, J.R.; Rommens, J.M.; Kerem, B.S.; Alon, N.; Rozmahel, R.; Grzelczak, Z.; Zielenski, J.; Lok, S.; Plavsic, N.; Chou, J.L.; Drumm, M.L.; Iannuzzi, M.C.; Collins, F.S.; Tsui, L.C. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989, 245 (4922), 1066-1072.

Licht, A.; Schneider, E. ATP binding cassette systems: structures, mechanisms, and functions. Cent. Eur. J. Biol. 2011, 6 (5), 785-801.

Rogan, M.P.; Stoltz, D.A.; Hornick, D.B. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. CHEST. 2011, 10 (139), 1480-1490.

Schmidt, B.Z.; Haaf, J.B.; Leal, T.; Noel, S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. ‎Clin. Pharmacol. 2016. 8, 127–140.

Eckford, P.D.; Ramjeesingh, M.; Molinski, S.; Pasyk, S.; Dekkers, J.F.; Li, C.; Ahmadi, S.; Ip, W.; Chung, T.E.; Du, K.; Yeger, H.; Beekman, J.; Gonska, T.; Bear, C.E. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem. Biol. 2014. 21, 666–678.

Chiaw, P.K.; Eckford, P.D.W.; Bear, C.E. Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy. Essays Biochem. 2011. 50, 233-248.

Wellhauser, L.; Chiaw, P.K.; Pasyk, S.; Li, C.; Ramjeesingh, M.; Bear, C.E. A Small-Molecule Modulator Interacts Directly with ∆Phe508-CFTR to Modify Its ATPase Activity and Conformational Stability. Mol. Pharmacol. 2009. 75 (6), 1430-1438.

Schwiebert, E.M.; Benos, D.J.; Egan, M.E.; Stutts, M.J.; Guggino, W.B. CFTR is a Conductance Regulator as well as a Chloride Channel. Physiological Reviews. 1999. 79 (suppl.1), S145-S166.

Conese, M; Ascenzionic, F.; Boyd, A.C.; Coutelle, C.; De Fino, I.; Smedt, S.; Rejman, J.; Rosenecker, J.; Schindelhauer, D.; Scholte, B.J. Gene and cell therapy for cystic fibrosis: From bench to bedside. J. Cyst. Fibros. 2011. 10 (suppl.2), S114-S128.

Di Saint’Agnese, P.A.; Darling R.C.; Perera, G.A.; Shea, E. Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas. Pediatrics. 1953, 12 (5), 549-563.

McKone, E.F.; Aitken, M.L. Cystic fibrosis: disease mechanisms and therapeutic targets. Drug Discovery Today: Disease Mechanisms. 2004, 1 (1), 137-143.

Schneider, E.K.; Reyes-Ortega, F.; Li, J.; Velkov, T. Can cystic fibrosis patients finally catch a breath with Lumacaftor/Ivacaftor? Clin. Pharmacol. Ther. 2017. 101 (1), 130-141.

Harutyunyan, M.; Huang, Y.; Mun, K.S.; Yang, F.; Arora, K.; Naren, A.P. Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations. Am. J. Physiol. Lung Cell Mol. Physiol. 2018. 314, L529–L543.

Quint, A.; Lerer, I.; Sagi, M.; Abeliovich, D. Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am. J. Med. Genet. A. 2005. 136A (3), 246–248.

Pedemonte, N.; Sonawane, N.D.; Taddei, A.; Hu, J.; Moran, O.Z.; Suen, Y.F.; Robins, L.I.; Dicus, C.W.; Willenbring, D.; Nantz, M.H.; Kurth, M.J.; Galietta, L.J.V.; Verkman, A.S. Phenylglycine and Sulfonamide Correctors of Defective ∆F508 and G551D Cystic Fibrosis Transmembrane Conductance Regulator Chloride-Channel Gating. Mol. Pharmacol. 2005. 67 (5), 1797-1807.

Yu, Y.C.; Miki, H.; Nakamura, Y.; Hanyuda, A.; Matsuzaki, Y.; Abe, Y.; Yasui, M.; Tanaka, K.; Hwang, T.C.; Bompadre, S.G.; Sohma, Y. Curcumin and genistein additively potentiate G551D-CFTR. J. Cyst. Fibros. 2011. 10, 243-252.

Dérand, R.; Pignoux, L.B.; Becq, F. The Cystic Fibrosis Mutation G551D Alters the Non-Michaelis-Menten Behavior of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel and Abolishes the Inhibitory Genistein Binding Site. J. Biol. Chem. 2002. 277(39), 35999-36004.

Welsh, M.J.; Smith, A.E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993. 73, 1251-1254.

Shoseyov, D.; Cymberknoh, M.C.; Kerem, E. Could you please pass the salt? Am. J. Respir. Crit. Care Med. 2011. 183, 1444-1446.

Narasimhan, M.; Cohen, R. New and investigational treatments in cystic fibrosis. Ther. Adv. Respir. Dis. 2011. 5 (4), 275-282.

Van Goor, F.; Hadida, S.; Grootenhuis, P.D.J.; Burton, B.; Cao, D.; Neuberger, T.; Turnbull, A.; Singh, A.; Joubran, J.; Hazlewood, A.; Zhou, J.; McCartney, J.; Arumugam, V.; Decker, C.; Yang, J.; Young, C.; Olson, E.R.; Wine, J.J.; Frizzell, R.A.; Ashlock, M.; Negulescu, P. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl. Acad. Sci.USA. 2009. 106 (44), 18825-18830.

Kaiser, J. New Cystic Fibrosis Drug Offers Hope, at a Price. Science. 2012. 335, 645.

Moss R.B. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest. 2002. 121, 55-63.

Konstan, M.W.; Flume, P.A.; Kappler, M.; Chiron, R.; Higgins, M.; Brockhaus, F.; Zhang, J.; Angyalosi, G.; He, E.; Geller, D.E. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J. Cyst. Fibros. 2011, 10, 54-61.

Flume, PA; O’Sullivan, B; Robinson KA; Goss, C.H.; Mogayzel, P.J.Jr, Willey-Courand, D.B.; Bujan, J.; Finder, J.; Lester, M.; Quittell, L.; Rosenblatt, R.; Vender, R.L.; Hazle, L.; Sabadosa, K.; Marshall, B. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J. Respir. Crit. Care Med. 2007. 176, 957-69.

Salvatore, D.; d’Andria, M. Effects of salmeterol on arterial oxyhemoglobin saturations in patients with cystic fibrosis. Pediatr. Pulmonol. 2002. 34 (1), 11-5.

Quan, J.M.; Tiddens, H.A.; Sy, J.P.; McKenzie, S.G.; Montgomery, M.D.; Robinson, P.J.; Wohl, M.E.; Konstan, M.W.; Pulmozyme Early Intervention Trial Study Group. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J. Pediatr. 2001. 139, 813-20.

Stern, R.C.; Eisenberg, J.D.; Wagener, J.S.; Ahrens, R.; Rock, M.; doPico, G.; Orenstein, D.M. A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency. Am. J. Gastroenterol. 2000, 95, 1932–8.

Misbahuddin, M.R.; Hussam, A.S.M.; Cystic fibrosis: current therapeutic targets and future approaches. Transl. Med. 2017. 15, 84.

Verkman, A.S.; Haggie, P.M.; Galietta, L.J.V. Application of green fluorescent protein-based chloride indicators for drug discovery by high-throughput screening. Rev. Fluor. 2004. 1, 85-98.

Wang, W.; Okeyo, G.O.; Tao, B.; Hong, J.S.; Kirk, K.L. Thermally unstable gating of the most common cystic fibrosis mutant channel (∆F508). J. Biol. Chem. 2011. 286 (49), 41937-41948.

U.S. Food and Drug Administration: Drugs@FDA, FDA Approved Drug Products.

Hadida, S.; Van Goor, F.; Zhou, J.; Arumugam, V.; McCartney, J.; Hazlewood, A.; Decker, C.; Negulescu, P.; Grootenhuis, P.D.J. Discovery of N‑(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator. J. Med. Chem. 2014. 57, 9776−9795.

Erlinger, S. Molecular repair of a defective CFTR protein in cystic fibrosis. Clin. Res. Hepatol. Gastroenterol. 2011. 35, 254-256.

Davies, J.C.; Wainwright, C.E.; Canny, G.J.; Chilvers, M.A.; Howenstine, M.S.; Munck, A.; Mainz, J.G.; Rodriguez, S.; Li, H.; Yen, K.; Ordon, C.L.; Ahrens, R.; on behalf of the VX08-770-103 (ENVISION) Study Group. Efficacy and safety of Ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D Mutation. Am. J. Respir. Crit. Care Med. 2013. 187, 1219-1225.

Heltshe, S.L.; Mayer-Hamblett, N.; Burns, J.L.; Khan, U.; Baines, A.; Ramsey, B.W.; Rowe, S. Pseudomonas aeruginosa in cystic fibrosis with G551D-CFTR treated with ivacaftor. Clin. Infect. Dis. 2015. 60 (5), 703–712.

Harbeson, S.L.; Morgan, A.J.; Liu, J.F.; Aslanian, A.M.; Nguyen, S.; Bridson, G.W.; Brummel, C.L.; Wu, L.; Tung, R.D.; Pilja, L.; Braman, V; Uttamsingh, V. Altering metabolic profiles of drugs by precision deuteration 2: discovery of a deuterated analog of ivacaftor with differentiated pharmacokinetics for clinical development. J. Pharmacol. Exp. Ther. 2017. 362, 359–367.

Becq, F.; Mall, M.A.; Sheppard, D.N.; Conese, M.; Moran, O.Z. Pharmacological therapy for cystic fibrosis: From bench to bedside. J. Cyst. Fibros. 2011. 10 (Suppl 2), S129–S145.

Dekkers, J.F.; Mourik, P.V.; Vonk, A.M.; Kruisselbrink, E; Berkers, G.; de Winter-de Groot, K.M.; Janssens, H.M.; Bronsveld, I.; Van der Ent, C.K.; de Jonge, H.R.; Beekman, J.M. Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations. J. Cyst. Fibros. 2016. 15, 568–578.

Okiyoneda, T.; Veit, G.; Dekkers, J.F.; Bagdany, M.; Soya, N.; Roldan, A.; Verkman, A.S.; Kurth, M.; Simon, A.; Hegedus, T.; Beekman, J.M.; Lukacs, G.L. Mechanism-based corrector combination restores DF508-CFTR folding and function. Nat. Chem. Biol. 2013. 9 (7), 444–454.

Hutt, D.M.; Loguercio,S. ; Campos, A.R.; Balch, W.E. A proteomic variant approach (ProVarA) for personalized medicine of inherited and somatic disease. J. Mol. Biol. 2018. 430(18 Pt A), 2951-2973.

Bulloch, M. N.; Hanna, C; Giovane, R. Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation. Expert Rev. Clin. Pharmacol. 2017. 10 (10), 1055–1072.

DeFrancesco, L. Drug pipeline: 3Q15. Nat. Biotechnol. 2015. 33 (11), 1126.

Brodsky, J.L.; Frizzell, R.A. A combination therapy for cystic fibrosis. Cell. 2015. 163, 17.

Molinski, S.V.; Ahmadi, S.; Ip, W.; Ouyang, H.; Villella, A.; Miller, J.P.; Lee, P.S.; Kulleperuma, K.; Du, K.; Di Paola, M.; Eckford, P.D.W.; Laselva, O.; Huan, L.J.; Wellhauser, L.; Li, E.; Ray, P.N.; Pomès, R.; Moraes, T. J.; Gonska, T.; Ratjen, F.; Bear, C.E. Orkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue. EMBO Mol. Med. 2017. 9 (9), 1224–1243.

Marengo, B.; Speciale, A.; Senatore, L.; Garibaldi, S.; Musumeci, F.; Nieddu, E.; Pollarolo, B.; Pronzato, M.A.; Schenone, S.; Mazzei, M.; Domenicotti, C. Matrine in association with FD-2 stimulates F508del-cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809. Mol. Med. Rep. 2017. 16, 8849-8853.

Chin, S.; Hung, M.; Won, A.; Wu, Y.-S.; Ahmadi, S.; Yang, D.; Elmallah, S.; Toutah, K.; Hamilton, C.M.; Young, R.N.; Viirre, R.D.; Yip, C.M.; Bear, C.E. Lipophilicity of the cystic fibrosis drug, Ivacaftor (VX-770), and its destabilizing effect on the major CF-causing mutation: F508del. Mol. Pharmacol. 2018. 94, 917–925.

Fukuda, R.; Okiyoneda, T. Peripheral protein quality control as a novel drug target for CFTR stabilizer. Front. Pharmacol. 2018. 9, 1100.

Moniz, S.; Sousa, M.; Moraes, B.J.; Mendes, A.I.; Palma, M.; Barreto, C.; Fragata, J.I.; Amaral, M.D.; Matos, P. HGF Stimulation of Rac1 signaling enhances pharmacological correction of the most prevalent cystic fibrosis mutant F508del-CFTR. ACS Chem. Biol. 2012. 8, 432–442.

Loureiro, C.A.; Matos, A.M.; Dias-Alvez, Â.; Pereira, J.F.; Uliyakina, I.; Barros, P.; Amaral, M.D.; Matos, P.M. A molecular switch in the scaffold NHERF1 enables misfolded CFTR to evade the peripheral quality control checkpoint. Sci. Signal. 2015. 8 (377), ra48.

Matos, A.M.; Gomes-Duarte, A.; Faria, M.; Barros, P.; Jordan, P.; Amaral, M.D.; Matos, P. Prolonged co-treatment with HGF sustains epithelial integrity and improves pharmacological rescue of phe508del-CFTR. Sci. Rep. 2018. 8 (1), 13026.

Alshafie, W.; Chappe, F.G.; Li, M.; Anini, Y.; Chappe, V.M. Vip Regulates Cftr Membrane Expression and Function in Calu-3 Cells by Increasing Its Interaction with Nherf1 and P-Erm in a Vpac1- and Pkcepsilon-Dependent Manner. Am. J. Physiol. Cell Physiol. 2014. 307, C107–C119.

Marozkina, N.V.; Yemen, S.; Borowitz, M.; Liu, L.; Plapp, M.; Sun, F.; Islam, R.; Erdmann-Gilmore, P.; Townsend, R.R.; Lichti, C.F.; Mantri, M.; Clapp, P.W.; Randell, S.H.; Gaston, B.; Zaman, K. Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proc. Natl. Acad. Sci. USA 2010. 107, 11393–11398.

Bergeron, C.; Cantin, A.M. New therapies to correct the cystic fibrosis basic defect. Int. J. Mol. Sci. 2021. 22 (12), 6193.

Giuliano, K.A.; Wachi, S.; Drew, L.; Dukovski, D.; Green, O.; Bastos, C.; Cullen, M.D.; Hauck, S.; Tait, B.D.; Munoz, B.; Lee, P.; Miller, J.P. Use of a high-throughput phenotypic screening strategy to identify amplifiers, a novel pharmacological class of small molecules that exhibit functional synergy with potentiators and correctors. SLAS Discovery. 2018. 23 (2), 111–121.

Shteinberg, M.; Haq, I.J.; Polineni, D.; Davies, J.C. Cystic fibrosis. Lancet. 2021. 397(10290), 2195-2211.

Pranke, I.; Golec, A.; Hinzpeter, A.; Edelman, A.; Sermet-Gaudelus, I. Emerging therapeutic approaches for cystic fibrosis. From gene editing to personalized medicine. Front. Pharmacol. 2019. 10, 121.

Fajak, I.; Boeck, K.D. New horizons for cystic fibrosis treatment. Pharmacol. Ther. 2017. 170, 205-211.

Griesenbach, U.; Pytel, K.M.; Alton, E.W. Cystic fibrosis Gene therapy in the UK and elsewhere. Human Gene Therapy. 2015. 26, 266–275.

Cheng, H.; Zhang, F.; Ding, Y. CRISPR/Cas9 Delivery system engineering for genome editing in therapeutic applications. Pharmaceutics. 2021. 13 (10), 1649.

Schwank, G.; Koo, B.K.; Sasselli, V.; Dekkers, J.F.; Heo, I.; Demircan, T.; Sasaki, N.; Boymans, S.; Cuppen, E.; Van der Ent, C.K.; Nieuwenhuis, E.E.; Beekman, J.M.; Clevers, H. Functional repair of CFTR by CRISPR/Cas9 in intestinal stemcell organoids of cystic fibrosispatients. Cell Stem Cell. 2013. 13, 653–658.

Drevinek, P.; Pressler, T.; Cipolli, Z.M.; De Boeck, K.; Schwarz, C.; Bouisset, F.; Boff, M.; Henig, N.; Paquette-Lamontagne, N.; Montgomery, S.; Perquin, J.; Tomkinson, J.; den Hollander, W.; Elborn, J.S. Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis. J. Cyst. Fibros. 2020. 19 (1), 99-107.

King, J.A.; Nichols, A.L.; Bentley, S.; Carr, S.B.; Davies, J.C. An update on CFTR modulators as new therapies for cystic fibrosis. Paediatr. Drugs. 2022. 24, 321–333.

Nichols, D.P.; Paynter, A.C.; Heltshe, S.L.; Donaldson, S.H.; Frederick, C.A.; Freedman, S.D.; Gelfond, D.; Hoffman, L.R.; Kelly, A.; Narkewicz, M.R.; Pittman, J.E.; Ratjen, F.; Rosenfeld, M.; Sagel, S.D.; Schwarzenberg, S.J.; Singh, P.K.; Solomon, J.M.; Stalvey, M.S.; Clancy, J.P.; Kirby, S.; Van Dalfsen, J.M.; Kloster, M.H.; Rowe, S.M.; the PROMISE Study Group. Clinical effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis. A clinical trial. Am. J. Respir. Crit. Care Med. 2022. 205(5), 529-539.



  • There are currently no refbacks.

Copyright (c) 2022 Salma Aly Elmallah, Raafat Soliman

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Advances in Medical, Pharmaceutical and Dental Research
E-ISSN: 2812-4898
P-ISSN: 2812-488X 

Published by:

Academy Publishing Center (APC)
Arab Academy for Science, Technology and Maritime Transport (AASTMT)
Alexandria, Egypt