SPX-101 is a novel epithelial sodium channel–targeted therapeutic for cystic fibrosis that restores mucus transport

American Journal of Respiratory and Critical Care Medicine

Volumn 196, Issue 6, 2017, Pages 734-744

  Scott, David W ^a   Walker, Matthew P ^a   Sesma, Juliana ^a   Wu, Bryant ^a   Stuhlmiller, Timothy J ^a   Sabater, Juan R ^b   Abraham, William M ^b   Crowder, Timothy M ^a   Christensen, Dale J ^a,d   Tarran, Robert ^a,c  

^a Spyryx Biosciences   (United Kingdom)

^b MOUNT SINAI MEDICAL CENTER   (United States)

^c UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^d DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Cystic fibrosis; Epithelial sodium channel; Mucociliary clearance

Indexed keywords

AMILORIDE; EPITHELIAL SODIUM CHANNEL; EPITHELIAL SODIUM CHANNEL BLOCKING AGENT; PROTEIN; SHORT PALATE LUNG AND NASAL EPITHELIAL CLONE 1; SPX 101; TETRAMETHYLRHODAMINE; UNCLASSIFIED DRUG; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOTINYLATION; BRONCHIAL CELL LINE; CONTROLLED STUDY; CYSTIC FIBROSIS; DRUG BINDING; DRUG EFFICACY; DRUG TARGETING; EC50; EOSINOPHIL; EPITHELIUM CELL; FEMALE; GENETIC TRANSFECTION; HEK293T CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; MUCUS; NEUTROPHIL; NONHUMAN; OVINE MODEL; PRIORITY JOURNAL; SURVIVAL RATE; WESTERN BLOTTING; DRUG EFFECTS; MUCOCILIARY CLEARANCE; RESPIRATORY MUCOSA;

CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; EPITHELIAL SODIUM CHANNEL BLOCKERS; EPITHELIAL SODIUM CHANNELS; HUMANS; MUCOCILIARY CLEARANCE; RESPIRATORY MUCOSA;

EID: 85029682826     PISSN: 1073449X     EISSN: 15354970     Source Type: Journal    
DOI: 10.1164/rccm.201612-2445OC     Document Type: Article

References (49)

1. Riordan JR. CFTR function and prospects for therapy. Annu Rev Biochem 2008;77:701–726.
2. Donaldson SH, Boucher RC. Sodium channels and cystic fibrosis. Chest 2007;132:1631–1636.
3. Knowles M, Gatzy J, Boucher R. Relative ion permeability of normal and cystic fibrosis nasal epithelium. J Clin Invest 1983;71: 1410–1417.
4. Tarran R, Redinbo MR. Mammalian short palate lung and nasal epithelial clone 1 (SPLUNC1) in pH-dependent airway hydration. Int J Biochem Cell Biol 2014;52:130–135.
5. Althaus M. ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art. Curr Mol Pharmacol 2013;6:3–12.
6. Mall MA, Graeber SY, Stahl M, Zhou-Suckow Z. Early cystic fibrosis lung disease: role of airway surface dehydration and lessons from preventive rehydration therapies in mice. Int J Biochem Cell Biol 2014; 52:174–179.
7. Haq IJ, Gray MA, Garnett JP, Ward C, Brodlie M. Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets. Thorax 2016;71:284–287.
8. Ciofu O, Hansen CR, Høiby N. Respiratory bacterial infections in cystic fibrosis. Curr Opin Pulm Med 2013;19:251–258.
9. Cantin AM, Hartl D, Konstan MW, Chmiel JF. Inflammation in cystic fibrosis lung disease: pathogenesis and therapy. J Cyst Fibros 2015; 14:419–430.
10. Puchelle E, Bajolet O, Abély M. Airway mucus in cystic fibrosis. Paediatr Respir Rev 2002;3:115–119.
11. Bennett WD, Wu J, Fuller F, Balcazar JR, Zeman KL, Duckworth H, Donn KH, O’Riordan TG, Boucher RC, Donaldson SH. Duration of action of hypertonic saline on mucociliary clearance in the normal lung. J Appl Physiol (1985) 2015;118:1483–1490.
12. Yang C, Chilvers M, Montgomery M, Nolan SJ. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev 2016;4:CD001127.
13. Shteinberg M, Elborn JS. Use of inhaled tobramycin in cystic fibrosis. Adv Ther 2015;32:1–9.
14. Hurt K, Bilton D. Inhaled interventions in cystic fibrosis: mucoactive and antibiotic therapies. Respiration 2014;88:441–448.
15. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 2009;106: 18825–18830.
16. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011;108: 18843–18848.
17. Graham A, Hasani A, Alton EW, Martin GP, Marriott C, Hodson ME, Clarke SW, Geddes DM. No added benefit from nebulized amiloride in patients with cystic fibrosis. Eur Respir J 1993;6: 1243–1248.
18. Hofmann T, Senier I, Bittner P, Hüls G, Schwandt HJ, Lindemann H. Aerosolized amiloride: dose effect on nasal bioelectric properties, pharmacokinetics, and effect on sputum expectoration in patients with cystic fibrosis. J Aerosol Med 1997;10:147–158.
19. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med 2006;354: 241–250.
20. Hirsh AJ. Altering airway surface liquid volume: inhalation therapy with amiloride and hyperosmotic agents. Adv Drug Deliv Rev 2002;54: 1445–1462.
21. Hirsh AJ, Sabater JR, Zamurs A, Smith RT, Paradiso AM, Hopkins S, Abraham WM, Boucher RC. Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. J Pharmacol Exp Ther 2004;311:929–938.
22. O’Riordan TG, Donn KH, Hodsman P, Ansede JH, Newcomb T, Lewis SA, Flitter WD, White VS, Johnson MR, Montgomery AB, et al. Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: phase 1 trial of GS-9411. J Aerosol Med Pulm Drug Deliv 2014;27:200–208.
23. App EM, King M, Helfesrieder R, Köhler D, Matthys H. Acute and long-term amiloride inhalation in cystic fibrosis lung disease: a rational approach to cystic fibrosis therapy. Am Rev Respir Dis 1990;141: 605–612.
24. Rodgers HC, Knox AJ. The effect of topical benzamil and amiloride on nasal potential difference in cystic fibrosis. Eur Respir J 1999;14: 693–696.
25. Burrows EF, Southern KW, Noone PG. Sodium channel blockers for cystic fibrosis. Cochrane Database Syst Rev 2014;(4): CD005087.
26. Garcia-Caballero A, Rasmussen JE, Gaillard E, Watson MJ, Olsen JC, Donaldson SH, Stutts MJ, Tarran R. SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc Natl Acad Sci USA 2009;106:11412–11417.
27. Garland AL, Walton WG, Coakley RD, Tan CD, Gilmore RC, Hobbs CA, Tripathy A, Clunes LA, Bencharit S, Stutts MJ, et al. Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways. Proc Natl Acad Sci USA 2013;110:15973–15978.
28. Hobbs CA, Blanchard MG, Alijevic O, Tan CD, Kellenberger S, Bencharit S, Cao R, Kesimer M, Walton WG, Henderson AG, 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: L990–L1001.
29. Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC. Increased airway epithelial Na1 absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004;10:487–493.
30. Tarran R, Sabater JR, Clarke TC, Tan CD, Davies CM, Liu J, Yeung A, Garland AL, Stutts MJ, Abraham WM, et al. Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion. Am J Physiol Lung Cell Mol Physiol 2013;304:L746–L756.
31. Fulcher ML, Gabriel S, Burns KA, Yankaskas JR, Randell SH. Well-differentiated human airway epithelial cell cultures. Methods Mol Med 2005;107:183–206.
32. 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: 255–259.
33. Knowles M, Gatzy J, Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 1981;305:1489–1495.
34. Alton EW, Rogers DF, Logan-Sinclair R, Yacoub M, Barnes PJ, Geddes DM. Bioelectric properties of cystic fibrosis airways obtained at heart-lung transplantation. Thorax 1992;47: 1010–1014.
35. Wielpütz MO, Eichinger M, Zhou Z, Leotta K, Hirtz S, Bartling SH, Semmler W, Kauczor HU, Puderbach M, Mall MA. In vivo monitoring of cystic fibrosis-like lung disease in mice by volumetric computed tomography. Eur Respir J 2011;38:1060–1070.
36. Zhou Z, Duerr J, Johannesson B, Schubert SC, Treis D, Harm M, Graeber SY, Dalpke A, Schultz C, Mall MA. The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. J Cyst Fibros 2011;10(Suppl 2):S172–S182.
37. Zhou Z, Treis D, Schubert SC, Harm M, Schatterny J, Hirtz S, Duerr J, Boucher RC, Mall MA. Preventive but not late amiloride therapy reduces morbidity and mortality of lung disease in bENaC-overexpressing mice. Am J Respir Crit Care Med 2008;178:1245–1256.
38. Fellner RC, Terryah ST, Tarran R. Inhaled protein/peptide-based therapies for respiratory disease. Mol Cell Pediatr 2016;3:16.
39. Ghazanfari T, Elhissi AM, Ding Z, Taylor KM. The influence of fluid physicochemical properties on vibrating-mesh nebulization. Int J Pharm 2007;339:103–111.
40. Bangel N, Dahlhoff C, Sobczak K, Weber WM, Kusche-Vihrog K. Upregulated expression of ENaC in human CF nasal epithelium. J Cyst Fibros 2008;7:197–205.
41. Gaillard EA, Kota P, Gentzsch M, Dokholyan NV, Stutts MJ, Tarran R. Regulation of the epithelial Na1 channel and airway surface liquid volume by serine proteases. Pflugers Arch 2010; 460:1–17.
42. Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995;269:847–850.
43. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE. Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 2002;277: 8338–8345.
44. Wilke M, Buijs-Offerman RM, Aarbiou J, Colledge WH, Sheppard DN, Touqui L, Bot A, Jorna H, de Jonge HR, Scholte BJ. Mouse models of cystic fibrosis: phenotypic analysis and research applications. J Cyst Fibros 2011;10(Suppl 2):S152–S171.
45. Carvalho-Oliveira I, Scholte BJ, Penque D. What have we learned from mouse models for cystic fibrosis? Expert Rev Mol Diagn 2007;7: 407–417.
46. Gehrig S, Duerr J, Weitnauer M, Wagner CJ, Graeber SY, Schatterny J, Hirtz S, Belaaouaj A, Dalpke AH, Schultz C, et al. Lack of neutrophil elastase reduces inflammation, mucus hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am J Respir Crit Care Med 2014;189: 1082–1092.
47. Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP. Animal models of cystic fibrosis pathology: phenotypic parallels and divergences. Biomed Res Int 2016;2016:5258727.
48. Bienvenu T, Sermet-Gaudelus I, Burgel PR, Hubert D, Crestani B, Bassinet L, Dusser D, Fajac I. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010;181: 1078–1084.
49. Wu T, Huang J, Moore PJ, Little MS, Walton WG, Fellner RC, Alexis NE, Peter Di Y, Redinbo MR, Tilley SL, et al. Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor. Nat Commun 2017;8:14118.