Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis

Piotr Sklepkiewicz, Barbara A. Dymek*, Michal Mlacki, Robert Koralewski, Marzena Mazur, Patrycja Nejman-Gryz, Serdar Korur, Agnieszka Zagozdzon, Aleksandra Rymaszewska, Jan H. von der Thüsen, Anna M. Siwińska, Nazan Cemre Güner, Łukasz Cheda, Magdalena Paplinska-Goryca, Małgorzata Proboszcz, Thierry P.P. van den Bosch, Katarzyna Górska, Jakub Golab, Rafał M. Kamiński, Rafał KrenkeAdam Golebiowski, Karolina Dzwonek, Pawel Dobrzanski

*Corresponding author for this work

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Idiopathic pulmonary fibrosis (IPF) is a progressive and eventually fatal lung disease with a complex etiology. Approved drugs, nintedanib and pirfenidone, modify disease progression, but IPF remains incurable and there is an urgent need for new therapies. We identified chitotriosidase (CHIT1) as new driver of fibrosis in IPF and a novel therapeutic target. We demonstrate that CHIT1 activity and expression are significantly increased in serum (3-fold) and induced sputum (4-fold) from IPF patients. In the lungs CHIT1 is expressed in a distinct subpopulation of profibrotic, disease-specific macrophages, which are only present in patients with ILDs and CHIT1 is one of the defining markers of this fibrosis-associated gene cluster. To define CHIT1 role in fibrosis, we used the therapeutic protocol of the bleomycin-induced pulmonary fibrosis mouse model. We demonstrate that in the context of chitinase induction and the macrophage-specific expression of CHIT1, this model recapitulates lung fibrosis in ILDs. Genetic inactivation of Chit1 attenuated bleomycin-induced fibrosis (decreasing the Ashcroft scoring by 28%) and decreased expression of profibrotic factors in lung tissues. Pharmacological inhibition of chitinases by OATD-01 reduced fibrosis and soluble collagen concentration. OATD-01 exhibited anti-fibrotic activity comparable to pirfenidone resulting in the reduction of the Ashcroft score by 32% and 31%, respectively. These studies provide a preclinical proof-of-concept for the antifibrotic effects of OATD-01 and establish CHIT1 as a potential new therapeutic target for IPF.

Original languageEnglish
Article number174792
JournalEuropean Journal of Pharmacology
Publication statusPublished - 15 Mar 2022

Bibliographical note

Sources of funding:
Studies were supported by two projects: (1) “Development of a first-in-class small molecule drug candidate for treatment of idiopathic pulmonary fibrosis through chitotriosidase inhibition” (POIR.01.01.01-00-0551/15), acronym IPF and (2) “Preclinical research and clinical trials of a first-in class development candidate in therapy of asthma and inflammatory bowel disease” (POIR.01.01.01- 00–0168/15), acronym IBD – both co-funded by the National Center for Research and Development, Poland in the framework of European Funds Smart Growth. BAD was supported by the Ministry of Science and Higher Education, Poland (50//DW/2017/01/1).

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