Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis
Barbara Dymek,1,2 Piotr Sklepkiewicz,1 Michal Mlacki,1 Nazan Cemre Güner,1 Patrycja Nejman-Gryz,3 Katarzyna Drzewicka,1 Natalia Przysucha,3 Aleksandra Rymaszewska,1 Magdalena Paplinska-Goryca,3 Agnieszka Zagozdzon,1 Małgorzata Proboszcz,3 Łukasz Krzemiński,1 Jan H vo...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2022-09-01
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| Series: | Journal of Inflammation Research |
| Subjects: | |
| Online Access: | https://www.dovepress.com/pharmacological-inhibition-of-chitotriosidase-chit1-as-a-novel-therape-peer-reviewed-fulltext-article-JIR |
| _version_ | 1828173144214470656 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dymek B |
| collection | DOAJ |
| description | Barbara Dymek,1,2 Piotr Sklepkiewicz,1 Michal Mlacki,1 Nazan Cemre Güner,1 Patrycja Nejman-Gryz,3 Katarzyna Drzewicka,1 Natalia Przysucha,3 Aleksandra Rymaszewska,1 Magdalena Paplinska-Goryca,3 Agnieszka Zagozdzon,1 Małgorzata Proboszcz,3 Łukasz Krzemiński,1 Jan H von der Thüsen,4 Katarzyna Górska,3 Karolina Dzwonek,1 Zbigniew Zasłona,1 Pawel Dobrzanski,1 Rafał Krenke3 1Molecure SA, Warsaw, 02-089, Poland; 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-097, Poland; 3Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, 02-097, Poland; 4Department of Pathology, Erasmus Medical Center, Rotterdam, 3015 GD, the NetherlandsCorrespondence: Barbara Dymek, Żwirki i Wigury 101, Warsaw, 02-089, Poland, Tel +48 22 552 67 24, Email b.dymek@molecure.comIntroduction: 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: chitinase, OATD-01, granuloma, macrophages, interstitial lung disease |
| first_indexed | 2024-04-12T03:51:23Z |
| format | Article |
| id | doaj.art-01cbe3adcdd046dbb0b3b76db82965b1 |
| institution | Directory Open Access Journal |
| issn | 1178-7031 |
| language | English |
| last_indexed | 2024-04-12T03:51:23Z |
| publishDate | 2022-09-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Inflammation Research |
| spelling | doaj.art-01cbe3adcdd046dbb0b3b76db82965b12022-12-22T03:48:58ZengDove Medical PressJournal of Inflammation Research1178-70312022-09-01Volume 155621563478635Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for SarcoidosisDymek BSklepkiewicz PMlacki MGüner NCNejman-Gryz PDrzewicka KPrzysucha NRymaszewska APaplinska-Goryca MZagozdzon AProboszcz MKrzemiński Łvon der Thüsen JHGórska KDzwonek KZasłona ZDobrzanski PKrenke RBarbara Dymek,1,2 Piotr Sklepkiewicz,1 Michal Mlacki,1 Nazan Cemre Güner,1 Patrycja Nejman-Gryz,3 Katarzyna Drzewicka,1 Natalia Przysucha,3 Aleksandra Rymaszewska,1 Magdalena Paplinska-Goryca,3 Agnieszka Zagozdzon,1 Małgorzata Proboszcz,3 Łukasz Krzemiński,1 Jan H von der Thüsen,4 Katarzyna Górska,3 Karolina Dzwonek,1 Zbigniew Zasłona,1 Pawel Dobrzanski,1 Rafał Krenke3 1Molecure SA, Warsaw, 02-089, Poland; 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-097, Poland; 3Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, 02-097, Poland; 4Department of Pathology, Erasmus Medical Center, Rotterdam, 3015 GD, the NetherlandsCorrespondence: Barbara Dymek, Żwirki i Wigury 101, Warsaw, 02-089, Poland, Tel +48 22 552 67 24, Email b.dymek@molecure.comIntroduction: 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: chitinase, OATD-01, granuloma, macrophages, interstitial lung diseasehttps://www.dovepress.com/pharmacological-inhibition-of-chitotriosidase-chit1-as-a-novel-therape-peer-reviewed-fulltext-article-JIRchitinaseoatd-01granulomamacrophagesinterstitial lung disease |
| spellingShingle | 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 Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis Journal of Inflammation Research chitinase oatd-01 granuloma macrophages interstitial lung disease |
| title | Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis |
| title_full | Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis |
| title_fullStr | Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis |
| title_full_unstemmed | Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis |
| title_short | Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis |
| title_sort | pharmacological inhibition of chitotriosidase chit1 as a novel therapeutic approach for sarcoidosis |
| topic | chitinase oatd-01 granuloma macrophages interstitial lung disease |
| url | https://www.dovepress.com/pharmacological-inhibition-of-chitotriosidase-chit1-as-a-novel-therape-peer-reviewed-fulltext-article-JIR |
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