Inhaled Biologicals for the Treatment of Cystic Fibrosis

Author(s): Valentina Sala* , Alessandra Murabito , Alessandra Ghigo* .

Journal Name: Recent Patents on Inflammation & Allergy Drug Discovery

Volume 13 , Issue 1 , 2019

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Background: Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy.

Objective: The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs.

Methods: The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted.

Results: Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release.

Conclusion: Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.

Keywords: Alpha-1-antitrypsin, cystic fibrosis, CFTR, ENaC, nebulizer, rhDNase.

Angelis A, Tordrup D, Kanavos P. Socio-economic burden of rare diseases: A systematic review of cost of illness evidence. Health Policy 2015; 119(7): 964-79.
Syed BA, Hamad B. The cystic fibrosis drug market. Nat Rev Drug Discov 2014; 13(10): 721-2.
Elborn JS, Bell SC, Madge SL, Burgel P-R, Castellani C, Conway S, et al. Report of the European Respiratory Society/European Cystic Fibrosis Society Task Force on the care of adults with cystic fibrosis. Eur Respir J 2016; 47(2): 420-8.
Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003; 56(6): 588-99.
Fellner RC, Terryah ST, Tarran R. Inhaled protein/peptide-based therapies for respiratory disease. Mol Cell Pediatr 2016; 3(1): 16.
Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol 2007; 35(1): 116-29.
da Silva AL, Cruz FF, Rocco PRM, Morales MM. New perspectives in nanotherapeutics for chronic respiratory diseases. Biophys Rev 2017; 9(5): 793-803.
Arnold S, Balance D. Methods and compositions for treating Cystic Fibrosis. WO2015172046 2015.
Odolczyk N, Edelman A, Zielenkiewicz P, Faure-Kuzminska G. Methods and compositions for modifying cystic fibrosis transmembrane conductance regulator activity. WO2017187274 2017.
Pini A, Falciani C, Bracci L. Antimicrobial peptide, branched forms thereof and their use in the treatment of bacterial infections. WO2012010266 2012.
Pini A, Falciani C, Bracci L. Antimicrobial peptide, branched forms thereof and their use in the treatment of bacteria infections. US20130130969 2013.
Bracci L, Giuliani A, Pini A, Neri P. Antibacterial peptides and analogues thereof. US20090053151 2001.
McDermott A, Mangoni M. Esculentin 1a derivatives and uses thereof. US20150104492 2015.
Vazquez-Espinosa E, Marcos C, Alonso T, Giron RM, Gomez-Punter RM, Garcia-Castillo E, et al. Tobramycin inhalation powder (TOBI Podhaler) for the treatment of lung infection in patients with cystic fibrosis. Expert Rev Anti Infect Ther 2016; 14(1): 9-17.
Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest 2002; 109(5): 571-7.
Ratjen F. Restoring airway surface liquid in cystic fibrosis. N Engl J Med 2006; 354(3): 291-3.
Garty H, Palmer LG. Epithelial sodium channels: Function, structure, and regulation. Physiol Rev 1999; 77(2): 359-96.
Schwameis R, Eder S, Pietschmann H, Fischer B, Mascher H, Tzotzos S, et al. A FIM study to assess safety and exposure of inhaled single doses of AP301-A specific ENaC channel activator for the treatment of acute lung injury. J Clin Pharmacol 2014; 54(3): 341-50.
Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, et al. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995; 269(5225): 847-50.
Garcia-Caballero A, Rasmussen JE, Gaillard E, Watson MJ, Olsen JC, Donaldson SH, et al. SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc Natl Acad Sci USA 2009; 106(27): 11412-7.
Hobbs CA, Blanchard MG, Kellenberger S, Bencharit S, Cao R, Kesimer M, et al. Identification of SPLUNC1's ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airways. FASEB J 2012; 26(10): 4348-59.
Hobbs CA, Blanchard MG, Alijevic O, Tan CD, Kellenberger S, Bencharit S, et al. Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures. Am J Physiol Lung Cell Mol Physiol 2013; 305(12): 990-1001.
Tarran R, Stutts M, Donaldson S. Regulation of sodium channels by PLUNC proteins. US20140228276 2014.
Tarran R, Stutts M, Donaldson S. Regulation of sodium channels by PLUNC proteins. US20160159879 2016.
Butler R, Hunt T, Smith NJ. ENaC inhibitors for the treatment of cystic fibrosis. Pharm Pat Anal 2015; 4(1): 17-27.
Smith NJ, Solovay CF. Epithelial Na+ channel inhibitors for the treatment of cystic fibrosis. Pharm Pat Anal 2017; 6(4): 179-88.
Kim CS, Ahmad S, Wu T, Walton WG, Redinbo MR, Tarran R. SPLUNC1 is an allosteric modulator of the epithelial sodium channel FASEB J 2018.
Rollins BM, Garcia-Caballero A, Stutts MJ, Tarran R. SPLUNC1 expression reduces surface levels of the epithelial sodium channel (ENaC) in Xenopus laevis oocytes. Channels (Austin) 2010; 4(4): 255-9.
Garland AL, Walton WG, Coakley RD, Tan CD, Gilmore RC, Hobbs CA, et al. Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways. Proc Natl Acad Sci USA 2013; 110(40): 15973-8.
Scott DW, Walker MP, Sesma J, Wu B, Stuhlmiller TJ, Sabater JR, et al. SPX-101 is a novel epithelial sodium channel-targeted therapeutic for cystic fibrosis that restores mucus transport. Am J Respir Crit Care Med 2017; 196(6): 734-44.
Terryah ST, Fellner RC, Ahmad S, Moore PJ, Reidel B, Sesma JI, et al. Evaluation of a SPLUNC1-derived peptide for the treatment of cystic fibrosis lung disease. Am J Physiol Lung Cell Mol Physiol 2018; 314(1): 192-205.
Tarran R, Christensen D. Improved peptide inhibitors of sodium channels. WO2016057795 2016.
Tarran R, Wu T. Peptide inhibitors of calcium channels. WO2017147128 2017.
Kurbatova P, Bessonov N, Volpert V, Tiddens HA, Cornu C, Nony P, et al. Model of mucociliary clearance in cystic fibrosis lungs. J Theor Biol 2015; 372: 81-8.
Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004; 23(1): 146-58.
Berlow RB, Dyson HJ, Wright PE. Functional advantages of dynamic protein disorder. Febs Lett 2015; 589(19): 2433-40.
Hirsh AJ. Altering airway surface liquid volume: Inhalation therapy with amiloride and hyperosmotic agents. Adv Drug Deliv Rev 2002; 54(11): 1445-62.
Hirsh AJ, Molino BF, Zhang J, Astakhova N, Geiss WB, Sargent BJ, et al. Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: Drugs for cystic fibrosis and chronic bronchitis. J Med Chem 2006; 49(14): 4098-115.
Rubin BK, Williams RW. Aerosolized antibiotics for non-cystic fibrosis bronchiectasis. Respiration 2014; 88(3): 177-84.
Majewski P, Majchrzak-Gorecka M, Grygier B, Skrzeczynska-Moncznik J, Osiecka O, Cichy J. Inhibitors of serine proteases in regulating the production and function of neutrophil extracellular traps. Front Immunol 2016; 7: 261-6.
Griese M, Kappler M, Gaggar A, Hartl D. Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respir J 2008; 32(3): 783-95.
Greene CM, McElvaney NG. Proteases and antiproteases in chronic neutrophilic lung disease: Relevance to drug discovery. Br J Pharmacol 2009; 158(4): 1048-58.
Low TB, Greene CM, O’Neill SJ, McElvaney NG. Quantification and evaluation of the role of antielastin autoantibodies in the emphysematous lung. Pulm Med 2011; 8: 261-6.
Randell SH, Boucher RC. Effective mucus clearance is essential for respiratory health. Am J Respir Cell Mol Biol 2006; 35(1): 20-8.
Tsai YF, Hwang TL. Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 - 2014). Expert Opin Ther Pat 2015; 25(10): 1145-58.
Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, et al. Alpha1-antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J 2007; 29(2): 240-50.
Travis J. Structure, function, and control of neutrophil proteinases. Am J Med 1988; 84(6A): 37-42.
Gadek JE, Klein HG, Holland PV, Crystal RG. Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest 1981; 68(5): 1158-65.
Brinkman E, Hack C, Van DNI. Recombinant human alpha1- antitrypsin. US20120214747 2012.
Brinkman N, Bigler D, Bolli R, Foertsch V. Methods for purification of alpha-1-antitrypsin andapolipoprotein A-1. US8436152 (2013) & US8653245 (2014) & US8962802 2015.
Dinarello C, Crapo J, Kim S. Compositions, methods and uses for alpha-1 antitrypsin fusion molecules. US20140341899 2014.
Kee S, Cook P, Smith J, Fowler S, Weber D. Methods of treatment using alpha-1-antitrypsin compositions. US20150320846 2015.
Kumpalume P, Podmore A, Dalton J. Method for the purification of alpha-1-antitrypsin. US8580931 2013.
Lior Y, Geyra A, Lewis EC. Therapeutic compositions and uses of alpha1-antitrypsin: A patent review. Expert Opin Ther Pat 2016; 26(5): 581-9.
Chapman KR, Burdon JG, Piitulainen E, Sandhaus RA, Seersholm N, Stocks JM, et al. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): A randomised, double-blind, placebo-controlled trial. Lancet 2015; 386(9991): 360-8.
Brand P, Schulte M, Wencker M, Herpich CH, Klein G, Hanna K, et al. Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency. Eur Respir J 2009; 34(2): 354-60.
Gaggar A, Chen J, Chmiel JF, Dorkin HL, Flume PA, Griffin R, et al. Inhaled alpha1-proteinase inhibitor therapy in patients with cystic fibrosis. J Cyst Fibros 2016; 15(2): 227-33.
Kaner Z, Ochayon DE, Shahaf G, Baranovski BM, Bahar N, Mizrahi M, et al. Acute phase protein alpha1-antitrypsin reduces the bacterial burden in mice by selective modulation of innate cell responses. J Infect Dis 2015; 211(9): 1489-98.
McElvaney NG. Alpha-1 Antitrypsin therapy in cystic fibrosis and the lung disease associated with alpha-1 antitrypsin deficiency. Ann Am Thorac Soc 2016; 13: S191-6.
Kryczka J, Boncela J. Proteases revisited: Roles and therapeutic implications in fibrosis. Mediators Inflamm 2017; 25: 7015-24.
Vasconcellos CA, Allen PG, Wohl ME, Drazen JM, Janmey PA, Stossel TP. Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin. Science 1994; 263(5149): 969-71.
Lethem MI, James SL, Marriott C, Burke JF. The origin of DNA associated with mucus glycoproteins in cystic fibrosis sputum. Eur Respir J 1990; 3(1): 19-23.
Matthews LW, Spector S, Lemm J, Potter JL. Studies on pulmonary secretions. The over-all chemical composition of pulmonary secretions from patients with cystic fibrosis, bronchiectasis, and laryngectomy. Am Rev Respir Dis 1963; 88: 199-204.
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994; 331(10): 637-42.
Felgner P, Abai A, Manthorpe M. Composition and method for treating cystic fibrosis. WO1993003709 1993.
Wagener JS, Kupfer O. Dornase alfa (Pulmozyme). Curr Opin Pulm Med 2012; 18(6): 609-14.
Sawicki GS, Chou W, Raimundo K, Trzaskoma B, Konstan MW. Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients. J Cyst Fibros 2015; 14(6): 777-83.
Xie J, Adams LM, Zhao J, Gerken TA, Davis PB, Ma J. A short segment of the R domain of cystic fibrosis transmembrane Conductance regulator contains channel stimulatory and inhibitory activities that are separable by sequence modification. J Biol Chem 2002; 277(25): 23019-27.
Adams L, Davis P, Ma J. Enhancers of CFTR chloride channel function. WO2000050591 (2000) & AU2000032419 (2000) & US6770739 (2000) & US20040121957 2004.
Goldstein AL. From lab to bedside: Emerging clinical applications of thymosin alpha 1. Expert Opin Biol Ther 2009; 9(5): 593-608.
Romani L, Oikonomou V, Moretti S, Iannitti RG, D’Adamo MC, Villella VR, et al. Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med 2017; 23(5): 590-600.
Romani L, Garaci E. Thymosin alpha 1 for use in treatment of cystic fibrosis. US20180036381 (2018) & WO2016129005 (2016) & AU2016217473 (2016) & CA2976062 2018.
Tomati V, Caci E, Ferrera L, Pesce E, Sondo E, Cholon DM, et al. Thymosin alpha-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia. JCI Insight 2018; 3(3): 11-9.
Cheng J, Wang H, Guggino WB. Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem 2004; 279(3): 1892-8.
Cushing PR, Vouilleme L, Pellegrini M, Boisguerin P, Madden DR. A stabilizing influence: CAL PDZ inhibition extends the half-life of DeltaF508-CFTR. Angew Chem Int Ed Engl 2010; 49(51): 9907-11.
Roberts KE, Cushing PR, Boisguerin P, Madden DR, Donald BR. Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. PLOS Comput Biol 2012; 8(4)e1002477
Calista TI. Composition and methods of use for cell targeted inhibitors of the cystic fibrosis transmembrane regulator associated ligand. AU2015234367 2015.
Mallon AP, Alvin CBI. Compositions and methods of use for cell targeted inhibitors of the cystic fibrosis transmembrane regulator associated ligand. US20140296164 2014.
Hwang SM, Kim DD, Chung SJ, Shim CK. Delivery of ofloxacin to the lung and alveolar macrophages via hyaluronan microspheres for the treatment of tuberculosis. J Control Release 2008; 129(2): 100-6.
Ahmad Z, Sharma S, Khuller GK. Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis. Int J Antimicrob Agents 2005; 26(4): 298-303.
Cheow WS, Hadinoto K. Factors affecting drug encapsulation and stability of lipid-polymer hybrid nanoparticles. Colloids Surf B Biointerfaces 2011; 85(2): 214-20.
Changsan N, Chan HK, Separovic F, Srichana T. Physicochemical characterization and stability of rifampicin liposome dry powder formulations for inhalation. J Pharm Sci 2009; 98(2): 628-39.
Zaru M, Manca ML, Fadda AM, Antimisiaris SG. Chitosan-coated liposomes for delivery to lungs by nebulisation. Colloids Surf B Biointerfaces 2009; 71(1): 88-95.
Glazer P, Saltzman WM, Egan M, McNeer NA. Compositions and methods for treatment of cystic fibrosis. WO2017143061 2017.
d’Angelo I, Conte C, La Rotonda MI, Miro A, Quaglia F, Ungaro F. Improving the efficacy of inhaled drugs in cystic fibrosis: Challenges and emerging drug delivery strategies. Adv Drug Deliv Rev 2014; 75: 92-111.
Weers J, Tarara T. The PulmoSphere platform for pulmonary drug delivery. Ther Deliv 2014; 5(3): 277-95.
Stein SW, Thiel CG. The history of therapeutic aerosols: A chronological review. J Aerosol Med Pulm Drug Deliv 2017; 30(1): 20-41.
Ibrahim M, Verma R, Garcia-Contreras L. Inhalation drug delivery devices: Technology update. Med Devices (Auckl) 2015; 8: 131-9.
Griese M, Scheuch G. Delivery of alpha-1 antitrypsin to airways. Ann Am Thorac Soc 2016; 13(Suppl. 4): S346-51.
Geller DE, Weers J, Heuerding S. Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology. J Aerosol Med Pulm Drug Deliv 2011; 24(4): 175-82.
Weers J, Ung K, Le J, Rao N, Ament B, Axford G, et al. Dose emission characteristics of placebo PulmoSphere(R) particles are unaffected by a subject’s inhalation maneuver. J Aerosol Med Pulm Drug Deliv 2013; 26(1): 56-68.
Usmani OS, Biddiscombe MF, Yang S, Meah S, Oballa E, Simpson JK, et al. The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis. Respir Res 2018; 6(1): 25.
Hertel SP, Winter G, Friess W. Protein stability in pulmonary drug delivery via nebulization. Adv Drug Deliv Rev 2011; 93: 79-94.
Geller DE, Kesser KC. The I-neb adaptive aerosol delivery system enhances delivery of alpha1-antitrypsin with controlled inhalation. J Aerosol Med Pulm Drug Deliv 2010; 23(Suppl. 1): S55-9.
Fischer A, Stegemann J, Scheuch G, Siekmeier R. Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials. Eur J Med Res 2009; 14(Suppl. 4): 71-7.
Hertel S, Pohl T, Friess W, Winter G. Prediction of protein degradation during vibrating mesh nebulization via a high throughput screening method. Eur J Pharm Biopharm 2014; 87(2): 386-94.
Elhissi A. Liposomes for pulmonary drug delivery: The role of formulation and inhalation device design. Curr Pharm Des 2017; 23(3): 362-72.
Nikander K, von Hollen D, Larhrib H. The size and behavior of the human upper airway during inhalation of aerosols. Expert Opin Drug Deliv 2017; 14(5): 621-30.
Heinemann L, Baughman R, Boss A, Hompesch M. Pharmacokinetic and pharmacodynamic properties of a novel inhaled insulin. J Diabetes Sci Technol 2017; 11(1): 148-56.
Norris AW. Is Cystic Fibrosis related diabetes reversible? New data on CFTR potentiation and insulin secretion. Am J Respir Crit Care Med 2018.

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Year: 2019
Page: [19 - 26]
Pages: 8
DOI: 10.2174/1872213X12666181012101444

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