Personalized Medicine; a Potential Therapy for Cystic Fibrosis

Aqsa Ashraf, Muhammad Usman Ghani, Muhammad Umer Khan, Hafiz Muzzammel Rehman, Mahmood ul Hassan, Zohair Mehdi


Cystic Fibrosis (CF) is an inherited disorder caused by mutations in CFTR gene that codes for Cystic Fibrosis Transmembrane-conductance Receptor anion channel. It is an autosomal recessive disease which affects the cells that secrete sweat, mucous and digestive juice, making these fluids thick and sticky, thus plugging ducts and tubes of various organs. The CF mutations are classified into various classes (class I, II, III, IV, V and VI) based on the cellular phenotype and complexity of mutants. The knowledge and understanding of biology and mechanisms of defects that underlie Cystic fibrosis paved a way to the development of different therapeutic approaches for these mutation classes. Ivacaftor first CFTR potentiator (FDA approved in 2012) is mostly used for Class III and IV mutations. Trials in patients with homozygous F508del mutation, a most common type of CF mutation that involves protein processing defects, showed no improvement with Ivacaftor alone, therefore, a double-combination therapy involving potentiator-corrector i.e., Ivacaftor-Lumacaftor got approval in 2015 to treat patients homozygous for F508del mutation. Then Ivacaftor-Tezacaftor (corrector) combination therapy was approved in 2018 which showed improved tolerability as compared to lumacaftor. In 2019, Trikfta, a triple combination therapy, came into light. It increases CFTR activity and is substantially considered to work more effectively in patients homozygous for F508del mutation. Studies and clinical trials reveal the outperformance of Trikafta in other available therapies in terms of respiratory symptoms, lungs functionality and quality of life on a whole.

Keywords: Cystic Fibrosis (CF); Cystic Fibrosis Transmembrane Conductance regulator (CFTR); Ivacaftor; Lumacaftor; Tezacaftor; Trikafta     

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Bernardino AL, Lima CE, Zatz M. Analysis of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in patients with obstructive azoospermia. Genetics and molecular biology, (2003); 261-3.

Bradbury NA (2020) CFTR and Cystic Fibrosis: A Need for Personalized Medicine. In: Hamilton KL, Devor DC, editors. Studies of Epithelial Transporters and Ion Channels Physiology in Health and Disease. Cham: Springer. pp. 773-802.

Quinton PM. Chloride impermeability in cystic fibrosis. Nature, (1983); 301(5899): 421-422.

Riordan JR, Rommens JM, Kerem B-s, Alon N, Rozmahel R, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science, (1989); 245(4922): 1066-1073.

Kelly J. Environmental scan of cystic fibrosis research worldwide. Journal of Cystic Fibrosis, (2017); 16(3): 367-370.

Flume PA, Robinson KA, O'Sullivan BP, Finder JD, Vender RL, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respiratory care, (2009); 54(4): 522-537.

Alibakhshi R, Mohammadi A, Khamooshian S, Kazeminia M, Moradi K. CFTR gene mutation spectrum among 735 Iranian patients with cystic fibrosis: A comprehensive systematic review. Pediatric pulmonology, (2021); 56(12): 3644-3656.

Linsdell P. Functional architecture of the CFTR chloride channel. Molecular membrane biology, (2014); 31(1): 1-16.

Rowe S. Miller S, Sorscher EJ. Cystic fibrosis N Engl J Med, (2005); 3521992-2001.

Muallem D, Vergani P. ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator. Philosophical Transactions of the Royal Society B: Biological Sciences, (2009); 364(1514): 247-255.

Riordan JR. CFTR function and prospects for therapy. Annu Rev Biochem, (2008); 77701-726.

Vergani P. Lockless SW, Nairn AC, Gadsby DC. CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains Nature, (2005); 433876-880.

Gelman MS, Kannegaard ES, Kopito RR. A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. Journal of Biological Chemistry, (2002); 277(14): 11709-11714.

Sharma M, Pampinella F, Nemes C, Benharouga M, So J, et al. Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. The Journal of cell biology, (2004); 164(6): 923-933.

Kopp BT, Sarzynski L, Khalfoun S, Hayes Jr D, Thompson R, et al. Detrimental effects of secondhand smoke exposure on infants with cystic fibrosis. Pediatric Pulmonology, (2015); 50(1): 25-34.

Ghani MU, Sabar MF, Awan FI. WS21.03 Low-cost chain termination DNA sequencing PCR reaction to diagnose CFTR gene mutations. Journal of Cystic Fibrosis, (2022); 21S41-S42.

Pezzulo AA, Tang XX, Hoegger MJ, Abou Alaiwa MH, Ramachandran S, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature, (2012); 487(7405): 109-113.

Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. New England Journal of Medicine, (2015); 372(4): 351-362.

Madácsy T, Pallagi P, Maleth J. Cystic fibrosis of the pancreas: the role of CFTR channel in the regulation of intracellular Ca2+ signaling and mitochondrial function in the exocrine pancreas. Frontiers in Physiology, (2018); 1585.

Harutyunyan M, Huang Y, Mun K-S, Yang F, Arora K, et al. Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations. American Journal of Physiology-Lung Cellular and Molecular Physiology, (2018); 314(4): L529-L543.

Kopelman H, Durie P, Gaskin K, Weizman Z, Forstner G. Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis. New England Journal of Medicine, (1985); 312(6): 329-334.

Strazzabosco M, Fabris L, Spirli C. Pathophysiology of cholangiopathies. Journal of clinical gastroenterology, (2005); 39(4): S90-S102.

Ledder O, Haller W, Couper RT, Lewindon P, Oliver M. Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations. Journal of gastroenterology and hepatology, (2014); 29(12): 1954-1962.

Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, et al. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science, (2014); 345(6198): 818-822.

Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med, (2007); 58157-170.

Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Annals of human genetics, (2003); 67(5): 471-485.

Pranke I, Bidou L, Martin N, Blanchet S, Hatton A, et al. Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons. ERJ open research, (2018); 4(1).

Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, et al. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell, (1995); 83(1): 129-135.

Bradbury NA (2020) CFTR and cystic fibrosis: a need for personalized medicine. Studies of Epithelial Transporters and Ion Channels: Springer. pp. 547-604.

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, et al. The future of cystic fibrosis care: a global perspective. The Lancet Respiratory Medicine, (2020); 8(1): 65-124.

Reddy M, Quinton PM. Selective activation of cystic fibrosis transmembrane conductance regulator Cl-and HCO3-conductances. Jop, (2001); 2(4 Suppl): 212-218.

Beck S, Penque D, Garcia S, Gomes A, Farinha C, et al. Cystic fibrosis patients with the 3272‐26A→ G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane. Human mutation, (1999); 14(2): 133-144.

Ramalho AS, Lewandowska MA, Farinha CM, Mendes F, Gonçalves J, et al. Deletion of CFTR translation start site reveals functional isoforms of the protein in CF patients. Cellular Physiology and Biochemistry, (2009); 24(5-6): 335-346.

Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis: a novel class of mutation. Journal of Biological Chemistry, (1999); 274(31): 21873-21877.

Silvis MR, Picciano JA, Bertrand C, Weixel K, Bridges RJ, et al. A mutation in the cystic fibrosis transmembrane conductance regulator generates a novel internalization sequence and enhances endocytic rates. Journal of Biological Chemistry, (2003); 278(13): 11554-11560.

Shenoy A, Spyropoulos D, Peeke K, Smith D, Cellucci M, et al. Newborn Screening for Cystic Fibrosis: Infant and Laboratory Factors Affecting Successful Sweat Test Completion. International journal of neonatal screening, (2020); 7(1): 1.

Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. The Journal of pediatrics, (2008); 153(2): S4-S14.

Sontag MK, Lee R, Wright D, Freedenberg D, Sagel SD. Improving the sensitivity and positive predictive value in a cystic fibrosis newborn screening program using a repeat immunoreactive trypsinogen and genetic analysis. The Journal of Pediatrics, (2016); 175150-158. e151.

Baker MW, Groose M, Hoffman G, Rock M, Levy H, et al. Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14 years of newborn screening. Journal of Cystic Fibrosis, (2011); 10(4): 278-281.

Sontag MK, Wright D, Beebe J, Accurso FJ, Sagel SD. A new cystic fibrosis newborn screening algorithm: IRT/IRT1↑/DNA. The Journal of pediatrics, (2009); 155(5): 618-622.

Rock MJ, Makholm L, Eickhoff J. A new method of sweat testing: the CF Quantum® sweat test. Journal of Cystic Fibrosis, (2014); 13(5): 520-527.

Rogan MP, Stoltz DA, Hornick DB. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. Chest, (2011); 139(6): 1480-1490.

Lopes-Pacheco M. CFTR modulators: shedding light on precision medicine for cystic fibrosis. Frontiers in pharmacology, (2016); 7275.

Jih K-Y, Hwang T-C. Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proceedings of the National Academy of Sciences, (2013); 110(11): 4404-4409.

Yu H, Burton B, Huang C-J, Worley J, Cao D, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. Journal of Cystic Fibrosis, (2012); 11(3): 237-245.

Davis PB, Yasothan U, Kirkpatrick P. Ivacaftor. Nature reviews Drug discovery, (2012); 11(5): 349-351.

Deeks ED. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs, (2016); 76(12): 1191-1201.

Favia M, Gallo C, Guerra L, De Venuto D, Diana A, et al. Treatment of cystic fibrosis patients homozygous for F508del with lumacaftor-ivacaftor (Orkambi®) restores defective CFTR channel function in circulating mononuclear cells. International journal of molecular sciences, (2020); 21(7): 2398.

Sala MA, Jain M. Tezacaftor for the treatment of cystic fibrosis. Expert review of respiratory medicine, (2018); 12(9): 725-732.

Quintana-Gallego E, Delgado-Pecellín I, Acuña CC. CFTR protein repair therapy in cystic fibrosis. Archivos de Bronconeumología (English Edition), (2014); 50(4): 146-150.

Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. The lancet Respiratory medicine, (2014); 2(7): 527-538.

Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest, (2018); 154(2): 383-393.

Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, et al. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ open research, (2019); 5(2).

Zaher A, ElSaygh J, Elsori D, ElSaygh H, Sanni A. A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy. Cureus, (2021); 13(7).

Keating D, Marigowda G, Burr L, Daines C, Mall MA, et al. VX-445–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. New england journal of medicine, (2018); 379(17): 1612-1620.

Konstan MW, Wagener JS, VanDevanter DR, Pasta DJ, Yegin A, et al. Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. Journal of Cystic Fibrosis, (2012); 11(5): 405-411.

Haq I, Almulhem M, Soars S, Poulton D, Brodlie M. Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis. Pharmacogenomics and Personalized Medicine, (2022); 1591.

Duckers J, Lesher B, Thorat T, Lucas E, McGarry LJ, et al. Real-world outcomes of ivacaftor treatment in people with cystic fibrosis: a systematic review. Journal of clinical medicine, (2021); 10(7): 1527.

Mitchell RM, Jones AM, Stocking K, Foden P, Barry PJ. Longitudinal effects of ivacaftor and medicine possession ratio in people with the Gly551Asp mutation: a 5-year study. Thorax, (2021); 76(9): 874-879.

Guimbellot J, Baines A, Paynter A, Heltshe S, VanDalfsen J, et al. Long term clinical effectiveness of ivacaftor in people with the G551D CFTR mutation. Journal of Cystic Fibrosis, (2021); 20(2): 213-219.

Burgel P-R, Munck A, Durieu I, Chiron R, Mely L, et al. Real-life safety and effectiveness of lumacaftor–ivacaftor in patients with cystic fibrosis. American journal of respiratory and critical care medicine, (2020); 201(2): 188-197.

Benden C, Schwarz C. CFTR Modulator Therapy and Its Impact on Lung Transplantation in Cystic Fibrosis. Pulmonary Therapy, (2021); 7(2): 377-393.

Dagenais RV, Su VC, Quon BS. Real-world safety of CFTR modulators in the treatment of cystic fibrosis: a systematic review. Journal of clinical medicine, (2020); 10(01): 23.

Zainal Abidin N, Haq IJ, Gardner AI, Brodlie M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert opinion on pharmacotherapy, (2017); 18(13): 1363-1371.

Blanchet S, Cornu D, Argentini M, Namy O. New insights into the incorporation of natural suppressor tRNAs at stop codons in Saccharomyces cerevisiae. Nucleic acids research, (2014); 42(15): 10061-10072.

Konstan M, VanDevanter D, Rowe S, Wilschanski M, Kerem E, et al. Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: the international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). Journal of Cystic fibrosis, (2020); 19(4): 595-601.

Kerem E. ELX-02: An investigational read-through agent for the treatment of nonsense mutation-related genetic disease. Expert Opinion on Investigational Drugs, (2020); 29(12): 1347-1354.

Bell SC, Barry PJ, De Boeck K, Drevinek P, Elborn JS, et al. CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials. Journal of Cystic Fibrosis, (2019); 18(5): 700-707.


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