Recombinant Human Deoxyribonuclease I

  • Robert A. LazarusEmail author
  • Jeffrey S. Wagener†


Human deoxyribonuclease I (DNase I) is an endonuclease that catalyzes the hydrolysis of extracellular DNA and is just one of the numerous types of nucleases found in nature. The enzymatic mechanism for a single turnover is reasonably well understood based on biochemical and structural studies that are consistent with divalent metal ion dependent nonspecific nicking of a phosphodiester bond in one of the strands of double stranded DNA. Recombinant human DNase I (rhDNase I, rhDNase, Pulmozyme®, dornase alfa) has been expressed in mammalian cell culture in Chinese hamster ovary cells and developed clinically where it is aerosolized into the airways for treatment of pulmonary disease in patients with cystic fibrosis (CF). rhDNase I hydrolyzes the DNA in purulent sputum of CF patients and reduces sputum viscoelasticity. Reduction of high molecular weight DNA into smaller fragments by treatment with aerosolized rhDNase I has been proposed as the mechanism to reduce the mucus viscosity and improve mucus clearability from obstructed airways in patients. The improved clearance of the purulent mucus enhances pulmonary function and reduces recurrent exacerbations of respiratory symptoms. rhDNase I was approved for clinical use in 1993 and has been widely used as a safe and effective therapy for CF patients. The use of rhDNase I has also been investigated in other diseases where exogenous DNA has been implicated in the disease pathology.


Human deoxyribonuclease I Pulmozyme® Cystic fibrosis Dornase alfa 


  1. Ago H, Oda M, Takahashi M, Tsuge H, Ochi S, Katunuma N, Miyano M, Sakurai J (2006) Structural basis of the sphingomyelin phosphodiesterase activity in neutral sphingomyelinase from Bacillus cereus. J Biol Chem 281:16157–16167PubMedCrossRefGoogle Scholar
  2. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A (1992) Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study. JAMA 267:1947–1951PubMedCrossRefGoogle Scholar
  3. Altunhan H, Annagür A, Pekcan S, Ors R, Koç H (2012) Comparing the efficacy of nebulizer recombinant human DNase and hypertonic saline as monotherapy and combined treatment in the treatment of persistent atelectasis in mechanically ventilated newborns. Pediatr Int 54:131–136PubMedCrossRefGoogle Scholar
  4. Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, Kerrigan S, Gustafsson P, Ratjen F (2011) The effect of dornase alfa on ventilation in homogeneity in patients with cystic fibrosis. Eur Respir J 37:806–812PubMedCrossRefGoogle Scholar
  5. Andreeva A, Howorth D, Chandonia JM, Brenner SE, Hubbard TJ, Chothia C, Murzin AG (2008) Data growth and its impact on the SCOP database: new developments. Nucleic Acids Res 36:D419–D425PubMedCrossRefGoogle Scholar
  6. Apel F, Zychlinsky A, Kenny EF (2018) The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol 14:467–475PubMedCrossRefGoogle Scholar
  7. Armstrong JB, White JC (1950) Liquefaction of viscous purulent exudates by deoxyribonuclease. Lancet 2:739–742PubMedCrossRefGoogle Scholar
  8. Bakker EM, Volpi S, Salonini E, van der Wiel-Kooij EC, Sintnicolaas CJJCM, Hop WCJ, Assael BM, Merkus PJFM, Tiddens HAWM (2011) Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. Eur Respir J 38:1328–1335PubMedCrossRefGoogle Scholar
  9. Baranovskii AG, Buneva VN, Nevinsky GA (2004) Human deoxyribonucleases. Biochemistry (Mosc) 69:587–601CrossRefGoogle Scholar
  10. Bataillon V, Lhermitte M, Lafitte JJ, Pommery J, Roussel P (1992) The binding of amikacin to macromolecules from the sputum of patients suffering from respiratory diseases. J Antimicrob Chemother 29:499–508PubMedCrossRefGoogle Scholar
  11. Boogaard R, de Jongste JC, Merkus PJ (2007a) Pharma-cotherapy of impaired mucociliary clearance in non-CF pediatric lung disease. A review of the literature. Pediatr Pulmonol 42:989–1001PubMedCrossRefGoogle Scholar
  12. Boogaard R, Hulsmann AR, van Veen L, Vaessen-Verberne AA, Yap YN, Sprij AJ, Brinkhorst G, Sibbles B, Hendriks T, Feith SW, Lincke CR, Brandsma AE, Brand PL, Hop WC, de Hoog M, Merkus PJ (2007b) Recombinant human deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis. Chest 131:788–795PubMedCrossRefGoogle Scholar
  13. Brinkmann V (2018) Neutrophil extracellular traps in the second decade. J Innate Immun 10:414–421PubMedCrossRefGoogle Scholar
  14. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedPubMedCentralCrossRefGoogle Scholar
  15. Campbell VW, Jackson DA (1980) The effect of divalent cations on the mode of action of DNase I. The initial reaction products produced from covalently closed circular DNA. J Biol Chem 255:3726–3735PubMedGoogle Scholar
  16. Carpenter EP, Corbett A, Thomson H, Adacha J, Jensen K, Bergeron J, Kasampalidis I, Exley R, Winterbotham M, Tang C, Baldwin GS, Freemont P (2007) AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis. EMBO J 26:1363–1372PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chen WJ, Liao TH (2006) Structure and function of bovine pancreatic deoxyribonuclease I. Protein Pept Lett 13:447–453PubMedCrossRefGoogle Scholar
  18. Chernick WS, Barbero GJ, Eichel HJ (1961) In vitro evaluation of effect of enzymes on tracheobronchial secretions from patients with cystic fibrosis. Pediatrics 27:589–596PubMedGoogle Scholar
  19. Cimmino M, Nardone M, Cavaliere M, Plantulli A, Sepe A, Esposito V, Mazzarella G, Raia V (2005) Dornase alfa as postoperative therapy in cystic fibrosis sinonasal disease. Arch Otolaryngol Head Neck Surg 131:1097–1101PubMedCrossRefGoogle Scholar
  20. Cipolla D, Gonda I, Shire SJ (1994) Characterization of aerosols of human recombinant deoxyribonuclease I (rhDNase) generated by jet nebulizers. Pharm Res 11:491–498PubMedCrossRefGoogle Scholar
  21. Cools-Lartigue J, Spicer J, Najmeh S, Ferri L (2014) Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci 71:4179–4194PubMedCrossRefGoogle Scholar
  22. Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller-Kopman D, Rahman NM (2015) Pleural infection: past, present, and future directions. Lancet Respir Med 3:563–577PubMedCrossRefGoogle Scholar
  23. Dasgupta B, King M (1996) Reduction in viscoelasticity in cystic fibrosis sputum in vitro using combined treatment with nacystelyn and rhDNase. Pediatr Pulmonol 22:161–166PubMedCrossRefGoogle Scholar
  24. Davis JC Jr, Manzi S, Yarboro C, Rairie J, McInnes I, Averthelyi D, Sinicropi D, Hale VG, Balow J, Austin H, Boumpas DT, Klippel JH (1999) Recombinant human DNase I (rhDNase) in patients with lupus nephritis. Lupus 8:68–76CrossRefGoogle Scholar
  25. Davoodian K, Ritchings BW, Ramphal R, Bubb MR (1997) Gelsolin activates DNase I in vitro and cystic fibrosis sputum. Biochemistry 36:9637–9641PubMedCrossRefGoogle Scholar
  26. Demers M, Wagner DD (2014) NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost 40:277–283PubMedPubMedCentralCrossRefGoogle Scholar
  27. Desai M, Weller PH, Spencer DA (1995) Clinical benefit from nebulized human recombinant DNase in Kartagener’s syndrome. Pediatr Pulmonol 20:307–308PubMedCrossRefGoogle Scholar
  28. Dilmen U, Karagol BS, Oguz SS (2011) Nebulized hypertonic saline and recombinant human DNase in the treatment of pulmonary atelectasis in newborns. Pediatr Int 53:328–331PubMedCrossRefGoogle Scholar
  29. Dlakic M (2000) Functionally unrelated signalling proteins contain a fold similar to Mg2+-dependent endonucleases. Trends Biochem Sci 25:272–273PubMedCrossRefGoogle Scholar
  30. Eisenberg JD, Aitken ML, Dorkin HL, Harwood IR, Ramsey BW, Schidlow DV, Wilmott RW, Wohl ME, Fuchs HJ, Christiansen DH, Smith AL (1997) Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. J Pediatr 131:118–124PubMedCrossRefGoogle Scholar
  31. El Abiad NM, Clifton S, Nasr SZ (2007) Long-term use of nebulized human recombinant DNase I in two siblings with primary ciliary dyskinesia. Respir Med 101:2224–2226PubMedCrossRefGoogle Scholar
  32. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT (2006) A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354:229–240PubMedCrossRefGoogle Scholar
  33. Evans CJ, Aguilera RJ (2003) DNase II: genes, enzymes and function. Gene 322:1–15PubMedCrossRefGoogle Scholar
  34. Fedakar A, Aydogdu C, Fedakar A, Ugurlucan M, Bolu S, Iskender M (2012) Safety of recombinant human deoxyribonuclease as a rescue treatment for persistent atelectasis in newborns. Ann Saudi Med 32:131–136PubMedPubMedCentralCrossRefGoogle Scholar
  35. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L, Rosenblatt R, Vender RL, Hazle L, Sabadosa K, Marshall B (2007) Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 176:957–969PubMedCrossRefGoogle Scholar
  36. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME (1994) Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 331:637–642PubMedCrossRefGoogle Scholar
  37. Geller DE, Eigen H, Fiel SB, Clark A, Lamarre AP, Johnson CA, Konstan MW (1998) Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Pediatr Pulmonol 25:83–87PubMedCrossRefGoogle Scholar
  38. Gilbert CR, Gorden JA (2017) Use of intrapleural tissue plasminogen activator and deoxyribonuclease in pleural space infections: an update on alternative regimens. Curr Opin Pulm Med 23:371–375PubMedCrossRefGoogle Scholar
  39. Gonda I (1990) Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract. Crit Rev Ther Drug Carrier Syst 6:273–313PubMedGoogle Scholar
  40. Gray RD, McCullagh BN, McCray PB (2015) NETs and CF lung disease: current status and future prospects. Antibiotics 4:62–75PubMedPubMedCentralCrossRefGoogle Scholar
  41. Green JD (1994) Pharmaco-toxicological expert report Pulmozyme rhDNase Genentech, Inc. Hum Exp Toxicol 13:S1–S42PubMedCrossRefGoogle Scholar
  42. Gueroult M, Picot D, Abi-Ghanem J, Hartmann B, Baaden M (2010) How cations can assist DNase I in DNA binding and hydrolysis. PLoS Comput Biol 6:e1001000PubMedPubMedCentralCrossRefGoogle Scholar
  43. Guggino WB, Stanton BA (2006) New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol 7:426–436PubMedCrossRefGoogle Scholar
  44. Gupta S, Kaplan MJ (2016) The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol 12:402–413PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 107:9813–9818CrossRefGoogle Scholar
  46. Hawes MC, Wen F, Elquza E (2015) Extracellular DNA: a bridge to cancer. Cancer Res 75:4260–4264PubMedCrossRefGoogle Scholar
  47. Hendriks T, de Hoog M, Lequin MH, Devos AS, Merkus PJ (2005) DNase and atelectasis in non-cystic fibrosis pediatric patients. Crit Care 9:R351–R356PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hitchcock SE, Carisson L, Lindberg U (1976) Depolymerization of F-actin by deoxyribonuclease I. Cell 7:531–542PubMedCrossRefGoogle Scholar
  49. Honda M, Kubes P (2018) Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol 15:206–221PubMedCrossRefGoogle Scholar
  50. Horton NC (2008) DNA nucleases. In: Rice PA, Correll CC (eds) Protein-nucleic acid interactions: structural biology. Royal Society of Chemistry Publishing, Cambridge, pp 333–363CrossRefGoogle Scholar
  51. Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, Wu M, Chernick MS, Crystal RG (1992) A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med 326:812–815PubMedCrossRefGoogle Scholar
  52. Jiménez-Alcázar M, Kim N, Fuchs TA (2017a) Circulating extracellular DNA: cause or consequence of thrombosis? Semin Thromb Hemost 243:553–561CrossRefGoogle Scholar
  53. Jiménez-Alcázar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, Bilyy R, Krenn V, Renné C, Renné T, Kluge S, Panzer U, Mizuta R, Mannherz HG, Kitamura D, Herrmann M, Napirei M, Fuchs TA (2017b) Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358:1202–1206PubMedCrossRefGoogle Scholar
  54. Jorch SK, Kubes P (2017) An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 23:279–287PubMedCrossRefGoogle Scholar
  55. Jubin V, Ranque S, Le bel NS, Sarles J, Dubus J-C (2010) Risk factors for Aspergillus colonization and allergic bronchopulmonary aspergillosis in children with cystic fibrosis. Pediatr Pulmonol 45:764–771PubMedCrossRefGoogle Scholar
  56. Kabsch W, Mannherz HG, Suck D, Pai EF, Holmes KC (1990) Atomic structure of the actin: DNase I complex. Nature 347:37–44PubMedCrossRefGoogle Scholar
  57. Kaplan JB, LoVetri K, Cardona ST, Madhyastha S, Sadovskaya I, Jabbouri S, Izano EA (2012) Recombinant human DNase I decreases biofilm and increases antimicrobial susceptibility in Staphylococci. J Antibiot (Tokyo) 65:73–77CrossRefGoogle Scholar
  58. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080PubMedCrossRefGoogle Scholar
  59. Keyel PA (2017) Dnases in health and disease. Dev Biol 429:1–11PubMedCrossRefGoogle Scholar
  60. King M, Dasgupta B, Tomkiewicz RP, Brown NE (1997) Rheology of cystic fibrosis sputum after in vitro treatment with hypertonic saline alone and in combination with recombinant human deoxyribonuclease I. Am J Respir Crit Care Med 156:173–177PubMedCrossRefGoogle Scholar
  61. Kominato Y, Ueki M, Iida R, Kawai Y, Nakajima T, Makita C, Itoi M, Tajima Y, Kishi K, Yasuda T (2006) Characterization of human deoxyribonuclease I gene (DNASE1) promoters reveals the utilization of two transcription-starting exons and the involvement of Sp1 in its transcriptional regulation. FEBS J 273:3094–3105PubMedCrossRefGoogle Scholar
  62. Konstan MW, Ratjen F (2012) Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J Cyst Fibros 11:78–83PubMedCrossRefGoogle Scholar
  63. Konstan MW, Byard PJ, Hoppel CL, Davis PB (1995) Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332:848–854PubMedCrossRefGoogle Scholar
  64. Konstan MW, Schluchter MD, Xue W, Davis PB (2007) Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med 176:1084–1089PubMedPubMedCentralCrossRefGoogle Scholar
  65. Konstan MW, VanDevanter DR, Rasouliyan L, Pasta DJ, Yegin A, Morgan WJ, Wagener JS (2010) Trends in the use of routine therapies in cystic fibrosis: 1995–2005. Pediatr Pulmonol 45:1167–1172PubMedPubMedCentralCrossRefGoogle Scholar
  66. Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, Morgan WJ (2011) Clinical use of dornase alfa is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol 46:545–553PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lachmann PJ (2003) Lupus and desoxyribonuclease. Lupus 12:202–206PubMedCrossRefGoogle Scholar
  68. Laskowski M Sr (1971) Deoxyribonuclease I. In: Boyer PD (ed) The enzymes, vol 4, 3rd edn. Academic, New York, pp 289–311Google Scholar
  69. Laube BL, Auci RM, Shields DE, Christiansen DH, Lucas MK, Fuchs HJ, Rosenstein BJ (1996) Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis. Am J Respir Crit Care Med 153:752–760PubMedCrossRefGoogle Scholar
  70. Law SM, Gray RD (2017) Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review. J Inflamm 14:29CrossRefGoogle Scholar
  71. Lazarides E, Lindberg U (1974) Actin is the naturally occurring inhibitor of deoxyribonuclease I. Proc Natl Acad Sci USA 71:4742–4746CrossRefGoogle Scholar
  72. Lazarus RA (2002) Human deoxyribonucleases. In: Creighton TE (ed) Wiley encyclopedia of molecular medicine. Wiley, New York, pp 1025–1028Google Scholar
  73. Lieberman J (1962) Enzymatic dissolution of pulmonary secretions. An in vitro study of sputum from patients with cystic fibrosis of pancreas. Am J Dis Child 104:342–348PubMedCrossRefGoogle Scholar
  74. Lieberman J (1968) Dornase aerosol effect on sputum viscosity in cases of cystic fibrosis. JAMA 205:312–313PubMedCrossRefGoogle Scholar
  75. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22:146–153PubMedPubMedCentralCrossRefGoogle Scholar
  76. MacKinnon R, Wheeler KI, Sokol J (2011) Endotracheal DNase for atelectasis in ventilated neonates. J Perinatol 31:799–801PubMedCrossRefGoogle Scholar
  77. Mainz JG, Schiller I, Ritschel C, Mentzel H-J, Riethmuller J, Koitschev A, Schneider G, Beck JF, Wiedemann B (2011) Sinonasal inhalation of dornase alfa in CF: a double-blind placebo-controlled cross-over pilot trial. Auris Nasus Larynx 38:220–227PubMedCrossRefGoogle Scholar
  78. Mainz JG, Schien C, Schiller I, Schädlich K, Koitschev A, Koitschev C, Riethmüller J, Graepler-Mainka U, Wiedemann B, Beck JF (2014) Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial. J Cyst Fibros 13:461–470PubMedCrossRefGoogle Scholar
  79. Martinod K, Wagner DD (2014) Thrombosis: tangled up in NETs. Blood 123(18):2768–2776PubMedPubMedCentralCrossRefGoogle Scholar
  80. Matthews LW, Specter S, Lemm J, Potter JL (1963) The over-all chemical composition of pulmonary secretions from patients with cystic fibrosis, bronchiectasis and laryngectomy. Am Rev Respir Dis 88:119–204Google Scholar
  81. McCoy K, Hamilton S, Johnson C (1996) Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Chest 110:889–895PubMedCrossRefGoogle Scholar
  82. Merza M, Hartman H, Rahman M, Hwaiz R, Zhang E, Renström E, Luo L, Mörgelin M, Regner S, Thorlacius H (2015) Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology 149:1920–1931PubMedCrossRefGoogle Scholar
  83. Mittal BB, Wang E, Sejpal S, Agulnik M, Mittal A, Harris K (2013) Effect of recombinant human deoxyribonuclease on oropharyngeal secretions in patients with head-and-neck cancers treated with radiochemotherapy. Int J Radiat Oncol Biol Phys 87:282–289PubMedCrossRefGoogle Scholar
  84. Mohler M, Cook J, Lewis D, Moore J, Sinicropi D, Championsmith A, Ferraiolo B, Mordenti J (1993) Altered pharmacokinetics of recombinant human deoxyribonuclease in rats due to the presence of a binding protein. Drug Metab Dispos 21:71–75PubMedGoogle Scholar
  85. Mol CD, Izumi T, Mitra S, Tainer JA (2000) DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination. Nature 403:451–456PubMedCrossRefGoogle Scholar
  86. Moore S (1981) Pancreatic DNase. In: Boyer PD (ed) The enzymes, vol 14, 3rd edn. Academic, New York, pp 281–296Google Scholar
  87. Morgan WJ, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, Konstan MW, Light MJ, Rabin HR, Regelmann WE, Schidlow DV, Stokes DC, Wohl ME, Kaplowitz H, Wyatt MM, Stryker S (1999) Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada. Pediatr Pulmonol 28:231–241PubMedCrossRefGoogle Scholar
  88. ten Berge M, Brinkhorst G, Kroon AA, de Jongste JC (1999) DNase treatment in primary ciliary dyskinesia—assessment by nocturnal pulse oximetry. Pediatr Pulmonol 27:59–61PubMedCrossRefGoogle Scholar
  89. Nasr SZ, Strouse PJ, Soskolne E, Maxvold NJ, Garver KA, Rubin BK, Moler FW (2001) Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest 120:203–208PubMedCrossRefGoogle Scholar
  90. O’Donnell AE, Barker AF, Ilowite JS, Fick RB (1998) Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 113:1329–1334PubMedCrossRefGoogle Scholar
  91. Pan CQ, Lazarus RA (1997) Engineering hyperactive variants of human deoxyribonuclease I by altering its functional mechanism. Biochemistry 36:6624–6632PubMedCrossRefGoogle Scholar
  92. Pan CQ, Lazarus RA (1999) Ca2+-dependent activity of human DNase I and its hyperactive variants. Protein Sci 8:1780–1788PubMedPubMedCentralCrossRefGoogle Scholar
  93. Pan CQ, Ulmer JS, Herzka A, Lazarus RA (1998a) Mutational analysis of human DNase I at the DNA binding interface: implications for DNA recognition, catalysis, and metal ion dependence. Protein Sci 7:628–636PubMedPubMedCentralCrossRefGoogle Scholar
  94. Pan CQ, Dodge TH, Baker DL, Prince WS, Sinicropi DV, Lazarus RA (1998b) Improved potency of hyperactive and actin-resistant human DNase I variants for treatment of cystic fibrosis and systemic lupus erythematosus. J Biol Chem 273:18374–18381PubMedCrossRefGoogle Scholar
  95. Pan CQ, Sinicropi DV, Lazarus RA (2001) Engineered properties and assays for human DNase I mutants. Methods Mol Biol 160:309–321PubMedGoogle Scholar
  96. Park J, Wysocki RW, Amoozgar Z, Maiorino L, Fein MR, Jorns J, Schott AF, Kinugasa-Katayama Y, Lee Y, Won NH, Nakasone ES, Hearn SA, Küttner V, Qiu J, Almeida AS, Perurena N, Kessenbrock K, Goldberg MS, Egeblad M (2016) Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci Transl Med 8:361ra138PubMedPubMedCentralCrossRefGoogle Scholar
  97. Parsiegla G, Noguere C, Santell L, Lazarus RA, Bourne Y (2012) The structure of human DNase I bound to magnesium and phosphate ions points to a catalytic mechanism common to members of the DNase I-like superfamily. Biochemistry 51:10250–10258PubMedCrossRefGoogle Scholar
  98. Paul K, Rietschel E, Ballmann M, Griese M, Worlitzsch D, Shute J, Chen C, Schink T, Döring G, van Koningsbruggen S, Wahn U, Ratjen F (2004) Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med 169:719–725PubMedCrossRefGoogle Scholar
  99. Piccolo F, Popowicz N, Wong D, Lee YC (2015) Intrapleural tissue plasminogen activator and deoxyribonuclease therapy for pleural infection. J Thorac Dis 7:999–1008PubMedPubMedCentralGoogle Scholar
  100. Potter JL, Specter S, Matthews LW, Lemm J (1969) Studies on pulmonary secretions. 3. The nucleic acids in whole pulmonary secretions from patients with cystic fibrosis bronchiectasis and laryngectomy. Am Rev Respir Dis 99:909–915PubMedGoogle Scholar
  101. Prince WS, Baker DL, Dodge AH, Ahmed AE, Chestnut RW, Sinicropi DV (1998) Pharmacodynamics of recombinant human DNase I in serum. Clin Exp Immunol 113:289–296PubMedPubMedCentralCrossRefGoogle Scholar
  102. Puterman AS, Weinberg EG (1997) rhDNase in acute asthma. Pediatr Pulmonol 23:316–317PubMedGoogle Scholar
  103. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ, Wohl ME, Konstan MW (2001) A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 139:813–820PubMedCrossRefGoogle Scholar
  104. Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ (2011) Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med 365:518–526PubMedCrossRefGoogle Scholar
  105. Ramphal R, Lhermitte M, Filliat M, Roussel P (1988) The binding of anti-pseudomonal antibiotics to macromolecules from cystic fibrosis sputum. J Antimicrob Chemother 22:483–490PubMedCrossRefGoogle Scholar
  106. Ramsey BW, Astley SJ, Aitken ML, Burke W, Colin AA, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Schidlow DV, Wilmott RW, Wohl ME, Meyerson LJ, Shak S, Fuchs H, Smith AL (1993) Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am Rev Respir Dis 148:145–151PubMedCrossRefGoogle Scholar
  107. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev KM, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL (1999) Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 340:23–30PubMedCrossRefGoogle Scholar
  108. Ramsey BW, Davies J, NG ME, Tullis E, Bell SC, Dřevínek P, Griese M, EF MK, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS, VX08-770-102 Study Group (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. New Engl J Med 365:1663–1672PubMedCrossRefGoogle Scholar
  109. Raskin P (1968) Bronchospasm after inhalation of pancreatic dornase. Am Rev Respir Dis 98:697–698PubMedGoogle Scholar
  110. Raynor EM, Butler A, Guill M, Bent JP 3rd (2000) Nasally inhaled dornase alfa in the postoperative management of chronic sinusitis due to cystic fibrosis. Arch Otolaryngol Head Neck Surg 126:581–583PubMedCrossRefGoogle Scholar
  111. Ren CL, Pasta DJ, Rasouliyan L, Wagener JS, Konstan MW, Morgan WJ (2008) Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis. J Pediatr 153:746–751PubMedCrossRefGoogle Scholar
  112. Riethmueller J, Borth-Bruhns T, Kumpf M, Vonthein R, Wiskirchen J, Stern M, Hofbeck M, Baden W (2006) Recombinant human deoxyribonuclease shortens ventilation time in young, mechanically ventilated children. Pediatr Pulmonol 41:61–66PubMedCrossRefGoogle Scholar
  113. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins FS, Tsui LC (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073PubMedCrossRefGoogle Scholar
  114. Robinson M, Hemming AL, Moriarty C, Eberl S, Bye PT (2000) Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis. Pediatr Pulmonol 30:16–24PubMedCrossRefGoogle Scholar
  115. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA, Reis FJC, Higa LYS, de Castro Toledo AC Jr, Pahl M (2010) Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis—a one-year prospective study. Pediatr Pulmonol 45:874–882PubMedCrossRefGoogle Scholar
  116. Saiman L, Mayer-Hamblett N, Campbell P, Marshall BC (2005) Heterogeneity of treatment response to azithromycin in patients with cystic fibrosis. Am J Respir Crit Care Med 172:1008–1012PubMedCrossRefGoogle Scholar
  117. Sanders NN, Franckx H, De Boeck K, Haustraete J, De Smedt SC, Demeester J (2006) Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis. Thorax 61:962–968PubMedPubMedCentralCrossRefGoogle Scholar
  118. Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, Shi L (2012) Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol 47:44–52PubMedCrossRefGoogle Scholar
  119. Sawicki GS, Chou W, Raimundo K, Trzaskoma B, Konstan MW (2015) Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients. J Cyst Fibros 14:777–783PubMedCrossRefGoogle Scholar
  120. Scala M, Hoy D, Bautista M, Palafoutas JJ, Abubakar K (2017) Pilot study of dornase alfa (Pulmozyme) therapy for acquired ventilator-associated infection in preterm infants. Pediatr Pulmonol 52:787–791PubMedCrossRefGoogle Scholar
  121. Scherer T, Geller DE, Owyang L, Tservistas M, Keller M, Boden N, Kesser KC, Shire SJ (2011) A technical feasibility study of dornase alfa delivery with eFlow vibrating membrane nebulizers: aerosol characteristics and physicochemical stability. J Pharm Sci 100:98–109PubMedCrossRefGoogle Scholar
  122. Shah PI, Bush A, Canny GJ, Colin AA, Fuchs HJ, Geddes DM, Johnson CA, Light MC, Scott SF, Tullis DE, De Vault A, Wohl ME, Hodson ME (1995) Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment. Eur Respir J 8:954–958PubMedGoogle Scholar
  123. Shak S (1995) Aerosolized recombinant human DNase I for the treatment of cystic fibrosis. Chest 107:65S–70SPubMedCrossRefGoogle Scholar
  124. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL (1990) Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 87:9188–9192CrossRefGoogle Scholar
  125. Shiokawa D, Tanuma S (2001) Characterization of human DNase I family endonucleases and activation of DNase gamma during apoptosis. Biochemistry 40:143–152PubMedCrossRefGoogle Scholar
  126. Shire SJ (1996) Stability characterization and formulation development of recombinant human deoxyribonuclease I [Pulmozyme, (dornase alfa)]. In: Pearlman R, Wang YJ (eds) Pharmaceutical biotechnology: formulation, characterization and stability of protein drugs, vol 9. Plenum Press, New York, pp 393–426CrossRefGoogle Scholar
  127. Silverman RA, Foley F, Dalipi R, Kline M, Lesser M (2012) The use of rhDNAse in severely ill, non-intubated adult asthmatics refractory to bronchodilators: a pilot study. Respir Med 106:1096–1102PubMedCrossRefGoogle Scholar
  128. Simpson G, Roomes D, Reeves B (2003) Successful treatment of empyema thoracis with human recombinant deoxyribonuclease. Thorax 58:365–366PubMedPubMedCentralCrossRefGoogle Scholar
  129. Sinicropi DV, Lazarus RA (2001) Assays for human DNase I activity in biological matrices. Methods Mol Biol 160:325–333PubMedGoogle Scholar
  130. Sinicropi DV, Prince WS, Lofgren JA, Williams M, Lucas M, DeVault A (1994a) Sputum pharmacodynamics and pharmacokinetics of recombinant human DNase I in cystic fibrosis. Am J Respir Crit Care Med 149:A671Google Scholar
  131. Sinicropi D, Baker DL, Prince WS, Shiffer K, Shak S (1994b) Colorimetric determination of DNase I activity with a DNA-methyl green substrate. Anal Biochem 222:351–358PubMedCrossRefGoogle Scholar
  132. Suck D (1994) DNA recognition by DNase I. J Mol Recognit 7:65–70PubMedCrossRefGoogle Scholar
  133. Suri R (2005) The use of human deoxyribonuclease (rhDNase) in the management of cystic fibrosis. BioDrugs 19:135–144PubMedCrossRefGoogle Scholar
  134. Thornton RB, Wiertsema SP, Kirkham LS, Rigby PJ, Vijayasekaran S, Coates HL, Richmond PC (2013) Neutrophil extracellular traps and bacterial biofilms in middle ear effusion of children with recurrent acute otitis media—a potential treatment target. PLoS One 8:e53837PubMedPubMedCentralCrossRefGoogle Scholar
  135. Ulmer JS, Herzka A, Toy KJ, Baker DL, Dodge AH, Sinicropi D, Shak S, Lazarus RA (1996) Engineering actin-resistant human DNase I for treatment of cystic fibrosis. Proc Natl Acad Sci USA 93:8225–8229CrossRefGoogle Scholar
  136. VanDevanter DR, Craib ML, Pasta DJ, Millar SJ, Morgan WJ, Konstan MW (2018) Cystic fibrosis clinical characteristics asssoiciated with dornase alfa treatment regimen change. Pediatr Pulmonol 53:43–49PubMedCrossRefGoogle Scholar
  137. Vasconcellos CA, Allen PG, Wohl ME, Drazen JM, Janmey PA, Stossel TP (1994) Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin. Science 263:969–971PubMedCrossRefGoogle Scholar
  138. Wagener JS, Kupfer O (2012) Dornase alfa (pulmozyme). Curr Opin Pulm Med 18:609–614PubMedCrossRefGoogle Scholar
  139. Wagener JS, Rock MJ, McCubbin MM, Hamilton SD, Johnson CA, Ahrens RC (1998) Aerosol delivery and safety of recombinant human deoxyribonuclease in young children with cystic fibrosis: a bronchoscopic study. J Pediatr 133:486–491PubMedCrossRefGoogle Scholar
  140. Wang H, Morita M, Yang X, Suzuki T, Yang W, Wang J, Ito K, Wang Q, Zhao C, Bartlam M, Yamamoto T, Rao Z (2010) Crystal structure of the human CNOT6L nuclease domain reveals strict poly(A) substrate specificity. EMBO J 29:2566–2576PubMedPubMedCentralCrossRefGoogle Scholar
  141. Widlak P, Garrard WT (2005) Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. J Cell Biochem 94:1078–1087PubMedCrossRefGoogle Scholar
  142. Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ (1996) Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med 154:413–417PubMedCrossRefGoogle Scholar
  143. Wilmott RW, Amin RS, Colin AA, DeVault A, Dozor AJ, Eigen H, Johnson C, Lester LA, McCoy K, McKean LP, Moss R, Nash ML, Jue CP, Regelmann W, Stokes DC, Fuchs HJ (1996) Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations. Am J Respir Crit Care Med 153:1914–1917PubMedCrossRefGoogle Scholar
  144. Wolf E, Frenz J, Suck D (1995) Structure of human pancreatic DNase I at 2.2 Å resolution. Protein Eng 8:79CrossRefGoogle Scholar
  145. Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, Kahn CR, Wagner DD (2015) Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med 21:815–819PubMedPubMedCentralCrossRefGoogle Scholar
  146. Yang W (2011) Nucleases: diversity of structure, function and mechanism. Q Rev Biophys 44:1–93PubMedCrossRefGoogle Scholar
  147. Zahm JM, Girod de Bentzmann S, Deneuville E, Perrot-Minnot C, Dabadie A, Pennaforte F, Roussey M, Shak S, Puchelle E (1995) Dose-dependent in vitro effect of recombinant human DNase on rheological and transport properties of cystic fibrosis respiratory mucus. Eur Respir J 8:381–386PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Early Discovery BiochemistryGenentech Inc.South San FranciscoUSA
  2. 2.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA

Personalised recommendations