A Phase I/II Placebo-Controlled Randomized Pilot Clinical Trial of Recombinant Deoxyribonuclease (DNase) Eye Drops Use in Patients With Dry Eye Disease

Christine Mun, Shilpa Gulati, Sapna Tibrewal, Yi-Fan Chen, Seungwon An, Bayasgalan Surenkhuu, Ilangovan Raju, Morgan Buwick, Anna Ahn, Ji-Eun Kwon, Nour Atassi, Anubhav Pradeep, Damiano Rondelli, Sandeep Jain, Christine Mun, Shilpa Gulati, Sapna Tibrewal, Yi-Fan Chen, Seungwon An, Bayasgalan Surenkhuu, Ilangovan Raju, Morgan Buwick, Anna Ahn, Ji-Eun Kwon, Nour Atassi, Anubhav Pradeep, Damiano Rondelli, Sandeep Jain

Abstract

Purpose: To determine whether DNase eye drops have the potential to reduce signs and symptoms of dry eye disease (DED).

Methods: A placebo-controlled, randomized clinical trial was performed to compare the safety and efficacy of DNase eye drops 0.1% four times a day for 8 weeks in patients with severe tear deficient DED. The change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (Ocular Surface Disease Index [OSDI] score, corneal and conjunctival staining) were analyzed between baseline and week 8.

Results: Tolerability and adverse events were similar in placebo group and DNase group. Within the DNase group (but not placebo group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 compared with baseline. The OSDI score also showed a significant median reduction of 27.3 at week 8 compared with baseline within the DNase group. The median reduction in corneal staining and mucoid debris/strands was significantly greater in the DNase group as compared with the placebo group. In the DNase group, the median reduction in OSDI (-20.75) was more than placebo group (-8.43); however, the difference between groups was borderline significant.

Conclusions: In this pilot study, treatment of severe tear deficient DED patients with DNase eye drops appears safe, well tolerated, and has the potential to reduce the severity of signs and symptoms.

Translational relevance: Data from this pilot clinical trial demonstrate the therapeutic potential of DNase eye drops in dry eye disease, possibly due to degradation neutrophil extracellular traps (NETs) from the ocular surface.

Keywords: DNase; NETs; clinical trial; dry eye.

References

    1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15:276–283.
    1. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15:438–510.
    1. Sonawane S, Khanolkar V, Namavari A, et al. Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease. Invest Ophthalmol Vis Sci. 2012;53:8253–8263.
    1. McDermott AM. New insight into dry eye inflammation. Invest Ophthalmol Vis Sci. 2012;53:8264.
    1. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
    1. Cooper PR, Palmer LJ, Chapple IL. Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe? Periodontol. 2013;63:165–197.
    1. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189:2689–2695.
    1. Simon D, Simon HU, Yousefi S. Extracellular DNA traps in allergic, infectious, and autoimmune diseases. Allergy. 2013;68:409–416.
    1. Tibrewal S, Ivanir Y, Sarkar J, et al. Hyperosmolar stress induces neutrophil extracellular trap formation: implications for dry eye disease. Invest Ophthalmol Vis Sci. 2014;55:7961–7969.
    1. Tibrewal S, Sarkar J, Jassim SH, et al. Tear fluid extracellular DNA: diagnostic and therapeutic implications in dry eye disease. Invest Ophthalmol Vis Sci. 2013;54:8051–8061.
    1. Fujihara J, Yasuda T, Ueki M, Iida R, Takeshita H. Comparative biochemical properties of vertebrate deoxyribonuclease I. Comp Biochem Physiol B Biochem Mol Biol. 2012;163:263–273.
    1. Samejima K, Earnshaw WC. Trashing the genome: the role of nucleases during apoptosis. Nat Rev Mol Cell Biol. 2005;6:677–688.
    1. Pulmozyme (dornase alpha) inhalation solution (08/2010) In Pulmozyme® (dornase alfa) Cystic Fibrosis Treatment Information. ( ). Available at: Accessed October 25, 2014.
    1. Wagener JS, Kupfer O. Dornase alfa (Pulmozyme) Curr Opin Pulm Med. 2012;18:609–614.
    1. Eulitz D, Mannherz HG. Inhibition of deoxyribonuclease I by actin is to protect cells from premature cell death. Apoptosis. 2007;12:1511–1521.
    1. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000;118:615–621.
    1. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221–232.
    1. Schulze MM, Jones DA, Simpson TL. The development of validated bulbar redness grading scales. Optom Vis Sci. 2007;84:976–983.
    1. Miller KL, Walt JG, Mink DR, et al. Minimal clinically important difference for the ocular surface disease index. Arch Ophthalmol. 2010;128:94–101.
    1. Amparo F, Dastjerdi MH, Okanobo A, et al. Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 2013;131:715–723.
    1. Asbell PA, Maguire MG, Pistilli M, et al. Dry Eye Assessment and Management Study Research Group. n-3 Fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378:1681–1690.
    1. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013;11:246–258.
    1. Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G. Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clin Exp Immunol. 2014;177:134–141.
    1. Frese S, Diamond B. Structural modification of DNA--a therapeutic option in SLE? Nat Rev Rheumatol. 2011;7:733–738.
    1. Pisetsky DS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol. 2012;144:32–40.
    1. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–569.
    1. Hacker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med. 2000;192:595–600.
    1. Schnare M, Holt AC, Takeda K, Akira S, Medzhitov R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol. 2000;10:1139–1142.
    1. Saffarzadeh M, Juenemann C, Queisser MA, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One. 2012;7:e32366.
    1. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–1321.
    1. Reinholz M, Ruzicka T, Schauber J. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012;24:126–135.
    1. Song JS, Kang CM, Rhee CK, et al. Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis. Exp Lung Res. 2009;35:817–829.
    1. Yang C, Chilvers M, Montgomery M, Nolan SJ. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2016. 4:CD001127.
    1. Gray RD, McCullagh BN, McCray PB. NETs and CF lung disease: current status and future prospects. Antibiotics (Basel) 2015;4:62–75.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren