Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis

Barbara Dymek; Piotr Sklepkiewicz; Michal Mlacki; Nazan Cemre Güner; Patrycja Nejman-Gryz; Katarzyna Drzewicka; Natalia Przysucha; Aleksandra Rymaszewska; Magdalena Paplinska-Goryca; Agnieszka Zagozdzon; Małgorzata Proboszcz; Łukasz Krzemiński; Jan H von der Thüsen; Katarzyna Górska; Karolina Dzwonek; Zbigniew Zasłona; Pawel Dobrzanski; Rafał Krenke

doi:10.2147/JIR.S378357

Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis

J Inflamm Res. 2022 Sep 29:15:5621-5634. doi: 10.2147/JIR.S378357. eCollection 2022.

Authors

Barbara Dymek^{1

2}, Piotr Sklepkiewicz¹, Michal Mlacki¹, Nazan Cemre Güner¹, Patrycja Nejman-Gryz³, Katarzyna Drzewicka¹, Natalia Przysucha³, Aleksandra Rymaszewska¹, Magdalena Paplinska-Goryca³, Agnieszka Zagozdzon¹, Małgorzata Proboszcz³, Łukasz Krzemiński¹, Jan H von der Thüsen⁴, Katarzyna Górska³, Karolina Dzwonek¹, Zbigniew Zasłona¹, Pawel Dobrzanski¹, Rafał Krenke³

Affiliations

¹ Molecure SA, Warsaw, 02-089, Poland.
² Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-097, Poland.
³ Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, 02-097, Poland.
⁴ Department of Pathology, Erasmus Medical Center, Rotterdam, 3015 GD, the Netherlands.

Abstract

Introduction: Sarcoidosis is a systemic disease of unknown etiology characterized by granuloma formation in the affected tissues. The pathologically activated macrophages are causatively implicated in disease pathogenesis and play important role in granuloma formation. Chitotriosidase (CHIT1), macrophage-derived protein, is upregulated in sarcoidosis and its levels correlate with disease severity implicating CHIT1 in pathology.

Methods: CHIT1 was evaluated in serum and bronchial mucosa and mediastinal lymph nodes specimens from sarcoidosis patients. The therapeutic efficacy of OATD-01 was assessed ex vivo on human bronchoalveolar lavage fluid (BALF) macrophages and in vivo in the murine models of granulomatous inflammation.

Results: CHIT1 activity was significantly upregulated in serum from sarcoidosis patients. CHIT1 expression was restricted to granulomas and localized in macrophages. Ex vivo OATD-01 inhibited pro-inflammatory mediators' production (CCL4, IL-15) by lung macrophages. In the acute model of granulomatous inflammation in mice, OATD-01 showed anti-inflammatory effects reducing the percentage of neutrophils and CCL4 concentration in BALF. In the chronic model, inhibition of CHIT1 led to a decrease in the number of organized lung granulomas and the expression of sarcoidosis-associated genes.

Conclusion: In summary, CHIT1 activity was increased in sarcoidosis patients and OATD-01, a first-in-class CHIT1 inhibitor, demonstrated efficacy in murine models of granulomatous inflammation providing a proof-of-concept for its clinical evaluation in sarcoidosis.

Keywords: OATD-01; chitinase; granuloma; interstitial lung disease; macrophages.

Grants and funding

Studies were supported by three projects: (1) “Preclinical research and clinical trials of a first-in-class development candidate in the therapy of asthma and inflammatory bowel disease” (POIR.01.01.01-00-0168/15), acronym IBD, (2) “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, both co-financed by European Union through the European Regional Development Fund within the Smart Growth Operational Programme and (3) “Preclinical and clinical development of drug candidate OATD-01, for the treatment of sarcoidosis patients” (MAZOWSZE/0128/19), acronym SARCO, as part of the “Path for Mazovia” competition co-financed by the National Centre for Research and Development from national funds. BAD was supported by the Ministry of Science and Higher Education, Poland (50//DW/2017/01/1).