Inhibition of TMEM16 proteins to attenuate mucus secretion and to improve airway clearance

• Applicant: Professor Dr. Karl Kunzelmann
• Subject Area: Anatomy and Physiology ; Pneumology, Thoracic Surgery ; Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407638684

• Final Report Year: 2024

Final Report Abstract

The main conclusions from the present comprehensive study are: 1) TMEM16 proteins (anoctamins) are proinflammatory, prosecretory and proproliferative in airways, intestine, and other tissues. 2) Inhibitors of TMEM16 reduce inflammation, bronchoconstriction, and mucus secretion in airways and intestine while activators of TMEM16 show opposite effects. 3) Inhibitors of TMEM16A are beneficial in the treatment of inflammatory airway diseases such as asthma, COPD, CF, and COVID-19 in mouse and human. 4) We propose low dose systemic application of niclosamide or benzbromarone, or high topical aerosol application of either compound to reduce inflammation along with mucus hypersecretion, bronchospasm, and pulmonary arterial hypertension in asthma, COPD and CF. Niclosamide is proposed as a treatment in severe COVID-19 and other highly inflammatory airway diseases.

Publications

• COMPOUND FOR USE IN THE TREATMENT OF A DISEASE CHARACTERIZED BY DYSREGULATED MUCUS PRODUCTION AND/OR SECRETION: 19783538.2 - 1112 / 3843725
  Kunzelmann, Karl
  
• INHIBITION OF TMEM16A BY BENZBROMARONE, NICLOSAMIDE, AND DERIVATIVES THEREOF FORTREATING POLYCYSTIC KIDNEY DISEASE AND/OR POLYCYSTIC LIVER DISEASE: PCT Online Filing Version 3.51.000.266e MT/FOP 20141031/0.20.5.20
  Kunzelmann Karl; Buchholz, Björn & Schreiber, Rainer
  
• TMEM16A is indispensable for basal mucus secretion in airways and intestine. The FASEB Journal, 33(3), 4502-4512.
  Benedetto, Roberta; Cabrita, Inês; Schreiber, Rainer & Kunzelmann, Karl
  
• ADAM10 sheddase activation is controlled by cell membrane asymmetry. Journal of Molecular Cell Biology, 11(11), 979-993.
  Bleibaum, Florian; Sommer, Anselm; Veit, Martin; Rabe, Björn; Andrä, Jörg; Kunzelmann, Karl; Nehls, Christian; Correa, Wilmar; Gutsmann, Thomas; Grötzinger, Joachim; Bhakdi, Sucharit & Reiss, Karina
  
• Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways. Frontiers in Pharmacology, 10.
  Miner, Kent; Labitzke, Katja; Liu, Benxian; Wang, Paul; Henckels, Kathryn; Gaida, Kevin; Elliott, Robin; Chen, Jian Jeffrey; Liu, Longbin; Leith, Anh; Trueblood, Esther; Hensley, Kelly; Xia, Xing-Zhong; Homann, Oliver; Bennett, Brian; Fiorino, Mike; Whoriskey, John; Yu, Gang; Escobar, Sabine ... & Sullivan, John K.
  
• Niclosamide repurposed for the treatment of inflammatory airway disease. JCI Insight, 4(15).
  Cabrita, Inês; Benedetto, Roberta; Schreiber, Rainer & Kunzelmann, Karl
  
• Plasma membrane–localized TMEM16 proteins are indispensable for expression of CFTR. Journal of Molecular Medicine, 97(5), 711-722.
  Benedetto, Roberta; Ousingsawat, Jiraporn; Cabrita, Inês; Pinto, Madalena; Lérias, Joana R.; Wanitchakool, Podchanart; Schreiber, Rainer & Kunzelmann, Karl
  
• TMEM16A in Cystic Fibrosis: Activating or Inhibiting?. Frontiers in Pharmacology, 10.
  Kunzelmann, Karl; Ousingsawat, Jiraporn; Cabrita, Inês; Doušová, Tereza; Bähr, Andrea; Janda, Melanie; Schreiber, Rainer & Benedetto, Roberta
  
• Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A. International Journal of Molecular Sciences, 21(7), 2557.
  Centeio, Raquel; Cabrita, Inês; Benedetto, Roberta; Talbi, Khaoula; Ousingsawat, Jiraporn; Schreiber, Rainer; Sullivan, John K. & Kunzelmann, Karl
  
• TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents. Journal of Medical Genetics, 58(4), 247-253.
  Park, Julien H.; Ousingsawat, Jiraporn; Cabrita, Inês; Bettels, Ruth E.; Große-Onnebrink, Jörg; Schmalstieg, Christian; Biskup, Saskia; Reunert, Janine; Rust, Stephan; Schreiber, Rainer; Kunzelmann, Karl & Marquardt, Thorsten
  
• Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption. Pflügers Archiv - European Journal of Physiology, 472(10), 1507-1519.
  Benedetto, Roberta; Centeio, Raquel; Ousingsawat, Jiraporn; Schreiber, Rainer; Janda, Melanie & Kunzelmann, Karl
  
• CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A. International Journal of Molecular Sciences, 22(10), 5133.
  Centeio, Raquel; Ousingsawat, Jiraporn; Schreiber, Rainer & Kunzelmann, Karl
  
• Getting hands on a drug for Covid-19: Inhaled and Intranasal Niclosamide. The Lancet Regional Health - Europe, 4, 100094.
  Kunzelmann, Karl
  
• Mucus Release and Airway Constriction by TMEM16A May Worsen Pathology in Inflammatory Lung Disease. International Journal of Molecular Sciences, 22(15), 7852.
  Centeio, Raquel; Ousingsawat, Jiraporn; Cabrita, Inês; Schreiber, Rainer; Talbi, Khaoula; Benedetto, Roberta; Doušová, Tereza; Verbeken, Eric K.; De Boeck, Kris; Cohen, Isaac & Kunzelmann, Karl
  
• P. aeruginosa Induced Lipid Peroxidation Causes Ferroptotic Cell Death in Airways. Cellular Physiology and Biochemistry, 55(5), 590-604.
  Ousingsawat, J.; Schreiber, R.; Gulbins, E.; Kamler, M. & Kunzelmann, K.
  
• TMEM16A Mediates Mucus Production in Human Airway Epithelial Cells. American Journal of Respiratory Cell and Molecular Biology, 64(1), 50-58.
  Cabrita, Inês; Benedetto, Roberta; Wanitchakool, Podchanart; Lerias, Joana; Centeio, Raquel; Ousingsawat, Jiraporn; Schreiber, Rainer & Kunzelmann, Karl
  
• Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease. International Journal of Molecular Sciences, 23(3), 1085.
  Ousingsawat, Jiraporn; Centeio, Raquel; Cabrita, Inês; Talbi, Khaoula; Zimmer, Oliver; Graf, Moritz; Göpferich, Achim; Schreiber, Rainer & Kunzelmann, Karl
  
• Expression of SLC26A9 in Airways and Its Potential Role in Asthma. International Journal of Molecular Sciences, 23(6), 2998.
  Ousingsawat, Jiraporn; Centeio, Raquel; Schreiber, Rainer & Kunzelmann, Karl
  
• Paneth Cell Secretion in vivo Requires Expression of Tmem16a and Tmem16f. Gastro Hep Advances, 1(6), 1088-1098.
  Schreiber, Rainer; Cabrita, Ines & Kunzelmann, Karl
  
• The SLC26A9 inhibitor S9‐A13 provides no evidence for a role of SLC26A9 in airway chloride secretion but suggests a contribution to regulation of ASL pH and gastric proton secretion. The FASEB Journal, 36(11).
  Jo, Sungwoo; Centeio, Raquel; Park, Jinhong; Ousingsawat, Jiraporn; Jeon, Dong‐kyu; Talbi, Khaoula; Schreiber, Rainer; Ryu, Kunhi; Kahlenberg, Kristin; Somoza, Veronika; Delpiano, Livia; Gray, Michael A.; Amaral, Margarida D.; Railean, Violeta; Beekman, Jeffrey M.; Rodenburg, Lisa W.; Namkung, Wan & Kunzelmann, Karl
  
• Niclosamide, but not ivermectin, inhibits anoctamin 1 and 6 and attenuates inflammation of the respiratory tract. Pflügers Archiv - European Journal of Physiology, 476(2), 211-227.
  Ousingsawat, Jiraporn; Centeio, Raquel; Schreiber, Rainer & Kunzelmann, Karl
  
• SLC26A9 in airways and intestine: secretion or absorption?. Channels, 17(1).
  Kunzelmann, Karl; Centeio, Raquel; Ousingsawat, Jiraporn; Talbi, Khaoula; Seidler, Ursula & Schreiber, Rainer
  
• TMEM16A/F support exocytosis but do not inhibit Notch-mediated goblet cell metaplasia of BCi-NS1.1 human airway epithelium. Frontiers in Physiology, 14.
  Centeio, Raquel; Cabrita, Inês; Schreiber, Rainer & Kunzelmann, Karl
  
• Benzbromarone as adjuvant therapy for cystic fibrosis lung disease: a pilot clinical trial. Jornal Brasileiro de Pneumologia, e20230292.
  Friedrich, Frederico; Montiel, Petry Lucas; de Castro e. Garcia, Laura; Puerari, Pieta Marina; da Silva, Meneses Amanda; Braga, Bittencourt Luana; Fernandes, Xavier Luiza; Otávio, Brum Antunes Marcos; Kich, Grun, Lucas; Lumertz, Magali; Kunzelmann, Karl & Araujo, Pinto Leonardo
  
• Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine. Scientific Reports, 14(1).
  Ousingsawat, Jiraporn; Centeio, Raquel; Reyne, Nicole; McCarron, Alexandra; Cmielewski, Patricia; Schreiber, Rainer; diStefano, Gabriella; Römermann, Dorothee; Seidler, Ursula; Donnelley, Martin & Kunzelmann, Karl