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

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

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › Academic › peer-review

17 Citations (Scopus)

37 Downloads (Pure)

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.

Original language	English
Pages (from-to)	5621-5634
Number of pages	14
Journal	Journal of Inflammation Research
Volume	15
DOIs	https://doi.org/10.2147/JIR.S378357
Publication status	Published - 29 Sept 2022

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2022 Dymek et al.

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Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for SarcoidosisFinal published version, 7.56 MBLicence: CC BY-NC

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Dymek, B., Sklepkiewicz, P., Mlacki, M., Güner, N. C., Nejman-Gryz, P., Drzewicka, K., Przysucha, N., Rymaszewska, A., Paplinska-Goryca, M., Zagozdzon, A., Proboszcz, M., Krzemiński, Ł., von der Thüsen, J. H., Górska, K., Dzwonek, K., Zasłona, Z., Dobrzanski, P., & Krenke, R. (2022). Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis. Journal of Inflammation Research, 15, 5621-5634. https://doi.org/10.2147/JIR.S378357

@article{a523d64811e540dbb47c50d499491c06,

title = "Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis",

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{\textquoteright} 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.",

author = "Barbara Dymek and Piotr Sklepkiewicz and Michal Mlacki and G{\"u}ner, \{Nazan Cemre\} and Patrycja Nejman-Gryz and Katarzyna Drzewicka and Natalia Przysucha and Aleksandra Rymaszewska and Magdalena Paplinska-Goryca and Agnieszka Zagozdzon and Ma{\l}gorzata Proboszcz and {\L}ukasz Krzemi{\'n}ski and \{von der Th{\"u}sen\}, \{Jan H.\} and Katarzyna G{\'o}rska and Karolina Dzwonek and Zbigniew Zas{\l}ona and Pawel Dobrzanski and Rafa{\l} Krenke",

note = "Funding Information: 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 {\textquoteleft}first-in-class{\textquoteright} 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). Publisher Copyright: {\textcopyright} 2022 Dymek et al.",

year = "2022",

month = sep,

day = "29",

doi = "10.2147/JIR.S378357",

language = "English",

volume = "15",

pages = "5621--5634",

journal = "Journal of Inflammation Research",

issn = "1178-7031",

publisher = "Dove Medical Press Ltd",

}

Dymek, B, Sklepkiewicz, P, Mlacki, M, Güner, NC, Nejman-Gryz, P, Drzewicka, K, Przysucha, N, Rymaszewska, A, Paplinska-Goryca, M, Zagozdzon, A, Proboszcz, M, Krzemiński, Ł, von der Thüsen, JH, Górska, K, Dzwonek, K, Zasłona, Z, Dobrzanski, P & Krenke, R 2022, 'Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis', Journal of Inflammation Research, vol. 15, pp. 5621-5634. https://doi.org/10.2147/JIR.S378357

TY - JOUR

T1 - Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis

AU - Dymek, Barbara

AU - Sklepkiewicz, Piotr

AU - Mlacki, Michal

AU - Güner, Nazan Cemre

AU - Nejman-Gryz, Patrycja

AU - Drzewicka, Katarzyna

AU - Przysucha, Natalia

AU - Rymaszewska, Aleksandra

AU - Paplinska-Goryca, Magdalena

AU - Zagozdzon, Agnieszka

AU - Proboszcz, Małgorzata

AU - Krzemiński, Łukasz

AU - von der Thüsen, Jan H.

AU - Górska, Katarzyna

AU - Dzwonek, Karolina

AU - Zasłona, Zbigniew

AU - Dobrzanski, Pawel

AU - Krenke, Rafał

N1 - Funding Information: 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). Publisher Copyright: © 2022 Dymek et al.

PY - 2022/9/29

Y1 - 2022/9/29

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85139120531

U2 - 10.2147/JIR.S378357

DO - 10.2147/JIR.S378357

M3 - Article

C2 - 36199746

AN - SCOPUS:85139120531

SN - 1178-7031

VL - 15

SP - 5621

EP - 5634

JO - Journal of Inflammation Research

JF - Journal of Inflammation Research

ER -

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

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