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Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

Author

Listed:
  • Carlo C. Campa

    (University of Torino)

  • Rangel L. Silva

    (University of Torino
    University of São Paulo)

  • Jean P. Margaria

    (University of Torino)

  • Tracey Pirali

    (Università degli Studi del Piemonte Orientale “A. Avogadro”)

  • Matheus S. Mattos

    (Universidade Federal de Minas Gerais/UFMG)

  • Lucas R. Kraemer

    (Universidade Federal de Minas Gerais/UFMG)

  • Diego C. Reis

    (Universidade Federal de Minas Gerais/UFMG
    Universidade Federal de Minas Gerais/UFMG)

  • Giorgio Grosa

    (Università degli Studi del Piemonte Orientale “A. Avogadro”)

  • Francesca Copperi

    (University of Torino)

  • Eduardo M. Dalmarco

    (Universidade Federal de Santa Catarina/UFSC)

  • Roberto C. P. Lima-Júnior

    (University of Torino
    Universidade Federal do Ceará/UFC)

  • Silvio Aprile

    (Università degli Studi del Piemonte Orientale “A. Avogadro”)

  • Valentina Sala

    (University of Torino)

  • Federica Dal Bello

    (University of Torino)

  • Douglas Silva Prado

    (University of São Paulo)

  • Jose Carlos Alves-Filho

    (University of São Paulo)

  • Claudio Medana

    (University of Torino)

  • Geovanni D. Cassali

    (Universidade Federal de Minas Gerais/UFMG)

  • Gian Cesare Tron

    (Università degli Studi del Piemonte Orientale “A. Avogadro”
    Kither Biotech S.r.l.)

  • Mauro M. Teixeira

    (Universidade Federal de Minas Gerais/UFMG)

  • Elisa Ciraolo

    (University of Torino
    Max Delbrück Center for Molecular Medicine)

  • Remo C. Russo

    (Universidade Federal de Minas Gerais/UFMG
    Universidade Federal de Minas Gerais/UFMG)

  • Emilio Hirsch

    (University of Torino
    Kither Biotech S.r.l.)

Abstract

PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.

Suggested Citation

  • Carlo C. Campa & Rangel L. Silva & Jean P. Margaria & Tracey Pirali & Matheus S. Mattos & Lucas R. Kraemer & Diego C. Reis & Giorgio Grosa & Francesca Copperi & Eduardo M. Dalmarco & Roberto C. P. Lim, 2018. "Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07698-6
    DOI: 10.1038/s41467-018-07698-6
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