Big-Data enabled Repurposing of Clopidogrel for Focal Segmental Glomerulosclerosis using Network Biology

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. By leveraging big data, we have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified repurposing the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (p<0.01) and weight loss (p<0.01), and ameliorated histopathological damage (p<0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repurposing candidate for clinical trial in FSGS. This proof-of-concept study demonstrates the feasibility of translating compounds from our computational technology platform via pre-clinical verification to clinical phase II readiness.

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Conference

Publisher: REPO4EU

Publication date (Electronic, pub): 6 October 2023

Affiliations

[1 ] Delta 4 GmbH, Vienna (Austria);

[2 ] Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna (Austria) ( https://ror.org/05n3x4p02)

[3 ] Division of Pathology, Medical University of Vienna, Vienna (Austria) ( https://ror.org/05n3x4p02)

[4 ] Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (USA) ( https://ror.org/04drvxt59)

[5 ] Delta 4 GmbH, Vienna (Austria);;

[6 ] Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria ( https://ror.org/03pt86f80)

Author information

Christoph A. Gebeshuber https://orcid.org/0000-0003-3293-4572

Klaus Kratochwill https://orcid.org/0000-0003-0803-614X

Paul Perco https://orcid.org/0000-0003-2087-5691

Article

DOI: 10.58647/REXPO.23029

SO-VID: b334357c-9774-42bc-87be-14d6f78fcf61

License:

Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: RExPO23

Conference number: 2

Conference location: Stockholm, Sweden

Conference date: 25-26 October 2023

History

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REPO4EU

References

Gebeshuber Christoph A., Daniel-Fischer Lisa, Regele Heinz, Schachner Helga, Aufricht Christoph, Kornauth Christoph, Ley Matthias, Alper Seth L., Herzog Rebecca, Kratochwill Klaus, Perco Paul. Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis. Translational Research. Vol. 259:28–34. 2023. Elsevier BV. [Cross Ref]

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[1] Gebeshuber Christoph A., Daniel-Fischer Lisa, Regele Heinz, Schachner Helga, Aufricht Christoph, Kornauth Christoph, Ley Matthias, Alper Seth L., Herzog Rebecca, Kratochwill Klaus, Perco Paul. Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis. Translational Research. Vol. 259:28–34. 2023. Elsevier BV. [Cross Ref]