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      Big Data-Enabled Repurposing of Clopidogrel for Focal Segmental Glomerulosclerosis Using Network Biology

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            Abstract

            Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease characterized by glomerular lesions and damage to podocytes, terminally differentiated renal cells, that are part of the filtration apparatus in glomeruli. FSGS is often associated with nephrotic syndrome and may lead to end-stage renal failure. FSGS pathophysiology is complex with a number of molecular mechanisms being involved in its development and progression. We used a network-based drug repositioning approach to computationally screen for novel treatment options for FSGS in a systematic way. In brief, we first generated a network-based molecular pathobiology model for FSGS following previously established workflows. FSGS-associated molecular features (i.e., genes and proteins) were mapped onto a human protein–protein dependency network, and network clustering algorithms were used to identify dysregulated FSGS molecular mechanisms and biological processes. Key affected enriched mechanisms included glomerular filtration, cell adhesion and extracellular matrix derangements, inflammation, apoptosis, calcineurin signaling, renin–angiotensin–aldosterone system, and platelet activation as well as dysregulation of fibrinolysis. The network-based FSGS pathobiology model was subsequently used to computationally screen against a library of drug mechanism of action molecular models. The platelet inhibitor clopidogrel was identified as one of the top compounds significantly interfering with FSGS pathophysiology based on in silico graph alignment analysis. Due to its potential to beneficially interfere with key dysregulated molecular FSGS processes, its positive in vivo data in ameliorating renal sclerosis, and its favorable safety profile, clopidogrel appears as an attractive candidate for subsequent evaluation in clinical trials.

            Main article text

            Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease characterized by glomerular lesions and damage to podocytes, terminally differentiated renal cells, that are part of the filtration apparatus in glomeruli. FSGS is often associated with nephrotic syndrome and may lead to end-stage renal failure. 1 FSGS pathophysiology is complex with a number of molecular mechanisms being involved in its development and progression. There is currently no specific approved therapy for FSGS, and treatment regimens consist of renin–angiotensin–aldosterone system (RAAS) inhibitors, calcineurin inhibitors, and corticosteroids. 2 Steroid-resistant nephrotic syndrome, however, is an issue in clinical practice, and novel treatment options for patients with FSGS are needed. The dual endothelin and RAAS antagonist sparsentan is an example of a novel compound that showed beneficial impact on proteinuria levels in patients with FSGS in the DUPLEX trial, however not significantly impacting the key outcome parameter, namely estimated glomerular filtration rate. 3 The group of sodium/glucose cotransporter 2 (SGLT2) inhibitors has also shown benefit in the management of patients with FSGS. 4 SGLT2 inhibitors have initially been developed for people with diabetes and cardiovascular complications, but have in the meantime also been evaluated for patients with diabetic kidney disease and subsequently for patients with chronic kidney disease in general. Drug repositioning presents a viable strategy to broaden the therapeutic options for nephrologists in order to optimize treatment of patients with FSGS. 5

            We used a network-based drug repositioning approach to computationally screen for novel treatment options for FSGS in a systematic way ( Figure 1 ). 6,7 In brief, we first generated a network-based molecular pathobiology model for FSGS following previously established workflows. 810 FSGS-associated molecular features (i.e., genes and proteins) were mapped onto a human protein–protein dependency network, and network clustering algorithms were used to identify dysregulated FSGS molecular mechanisms and biological processes. Key affected enriched mechanisms included glomerular filtration, cell adhesion and extracellular matrix derangements, inflammation, apoptosis, calcineurin signaling, RAAS, and platelet activation as well as dysregulation of fibrinolysis. The network-based FSGS pathobiology model was subsequently used to computationally screen against a library of drug mechanism of action (MoA) molecular models. The platelet inhibitor clopidogrel was identified as one of the top compounds significantly interfering with FSGS pathophysiology based on in silico graph alignment analysis. Clopidogrel significantly attenuated weight loss and albuminuria in the adriamycin mouse model of FSGS and also beneficially affected sclerosis and tubular atrophy as determined in histopathological examination in vivo. 6 Clopidogrel appears as a very interesting drug candidate as the affected molecular targets and biological mechanisms that are beneficially influenced by its MoA appear to be rather complementary to the current standard-of-care FSGS treatment regimens, namely RAAS inhibitors, calcineurin inhibitors, and corticosteroids.

            Figure 1.

            Drug repositioning of clopidogrel for FSGS. Clopidogrel was identified as the lead candidate in a network-based computational drug screen. Clopidogrel was subsequently validated in the adriamycin mouse model of FSGS and is currently tested in the ClopiD4FSGS phase II clinical trial. FSGS, focal segmental glomerulosclerosis; RAAS, renin–angiotensin–aldosterone system.

            Based on these findings, a study plan was developed to test the impact of clopidogrel on FSGS progression in the ClopiD4FSGS study (EudraCT Nr: 2022-003313-11), a single-arm multicenter proof-of-concept 24-week phase II clinical trial. 11 Conduction of this trial is further supported by evidence from other research groups that discuss the beneficial impact of clopidogrel on renal fibrosis and chronic kidney disease. 12,13 In addition, nonadherence to antiplatelet drugs has been reported to be significantly associated with worse cardiorenal outcomes in patients with diabetes mellitus. 14

            In summary, we have identified the antiplatelet drug clopidogrel as a promising novel treatment option for patients with FSGS. Due to its potential to beneficially interfere with key dysregulated molecular FSGS processes, its positive in vivo data in ameliorating renal sclerosis, and its favorable safety profile, clopidogrel appears as an attractive candidate for subsequent evaluation in clinical trials.

            CONFLICTS OF INTEREST

            P. Perco, Christoph A. Gebeshuber, and M. Ley are employees of Delta4 GmbH. L. Daniel-Fischer was partly funded by a research grant from Delta4 GmbH. C. Aufricht is a co-founder of Delta4 GmbH and member of the scientific advisory board. K. Kratochwill is a co-founder of Delta4 GmbH and part of Delta4’s management team. Delta4 GmbH has filed the patent application entitled “CLOPIDOGREL FOR USE IN THE TREATMENT OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)” (WO/2022/117862 A1).

            ACKNOWLEDGEMENTS

            This work was originally presented at RExPO23, the 2nd International Conference on Systems Medicine, AI & Drug Repurposing in Stockholm, Sweden, October 25-26 2023.

            REFERENCES

            1. Shabaka A, Tato Ribera A, Fernández-Juárez G. Focal segmental glomerulosclerosis: State-of-the-art and clinical perspective. Nephron. 2020. Vol. 144:413–427

            2. de Cos M, Meliambro K, Campbell KN. Novel treatment paradigms: Focal segmental glomerulosclerosis. Kidney Int Rep. 2023. Vol. 8:30–35

            3. Rheault MN, Alpers CE, Barratt J, et al.. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N Engl J Med. 2023. Vol. 389:2436–2445

            4. Chan ATP, Tang SCW. Could SGLT2 inhibitors be the next ‘game changer’ in focal segmental glomerulosclerosis? Nephrol Dial Transplant. 2022. Vol. 37:1593–1594

            5. Shankland SJ, Jefferson JA, Wessely O. Repurposing drugs for diseases associated with podocyte dysfunction. Kidney Int. 2023. Vol. 104:455–462

            6. Gebeshuber CA, Daniel-Fischer L, Regele H, et al.. Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis. Transl Res. 2023. Vol. 259:28–34

            7. Perco P. Clopidogrel for use in the treatment of focal segmental glomerulosclerosis. US 2024/0016785 A1. 2024. https://ppubs.uspto.gov/dirsearch-public/print/downloadPdf/20240016785

            8. Heerspink HJL, Perco P, Mulder S, et al.. Canagliflozin reduces inflammation and fibrosis biomarkers: A potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019. Vol. 62:1154–1166

            9. Mayer B, Heinzel A, Lukas A, Perco P. Predictive biomarkers for linking disease pathology and drug effect. Curr Pharm Des. 2017. Vol. 23:29–54

            10. Boehm M, Bukosza EN, Huttary N, et al.. A systems pharmacology workflow with experimental validation to assess the potential of anakinra for treatment of focal and segmental glomerulosclerosis. PLoS One. 2019. Vol. 14:e0214332

            11. Daniel-Fischer L, Antlanger M, Cejka D, et al.. Clopidogrel for proteinuria reduction in focal segmental glomerulosclerosis: Phase 2 trial design. Kidney Int Rep. 2024. Vol. 9:478–481

            12. Chen J, Tang Y, Zhong Y, et al.. P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition. Mol Ther. 2022. Vol. 30:3017–3033

            13. Natale P, Palmer SC, Saglimbene VM, et al.. Antiplatelet agents for chronic kidney disease. Cochrane database Syst Rev. 2022. Vol. 2:CD008834

            14. Denicolò S, Reinstadler V, Keller F, et al.. Non-adherence to cardiometabolic medication as assessed by LC-MS/MS in urine and its association with kidney and cardiovascular outcomes in type 2 diabetes mellitus. Diabetologia. 2024. Vol. 67:1283–1294

            Author and article information

            Journal
            dr
            Drug Repurposing
            ScienceOpen (Berlin )
            2941-2528
            03 July 2024
            : 1
            : 1
            : e20240006
            Affiliations
            [1 ] Delta4 GmbH, Vienna, Austria;
            [2 ] Medical University of Innsbruck, Department of Internal Medicine IV, Innsbruck, Austria ( https://ror.org/03pt86f80)
            [3 ] Medical University of Vienna, Comprehensive Center for Pediatrics, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Vienna, Austria ( https://ror.org/05n3x4p02)
            Author notes
            *Correspondence to: Klaus Kratochwill, Delta4 GmbH, Alser Straße 23/30, 1080 Vienna, Austria. E-mail: klaus.kratochwill@ 123456delta4.ai
            Author information
            https://orcid.org/0000-0003-2087-5691
            https://orcid.org/0000-0003-0803-614X
            Article
            10.58647/DRUGREPO.24.1.0006
            68165e93-f9ff-40aa-9556-0cb558990eab
            2024 The Author(s).

            This work has been published open access under Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com.

            History
            : 11 June 2024
            : 13 June 2024
            Page count
            Figures: 1, References: 14, Pages: 3
            Categories

            drug repurposing,focal segmental glomerulosclerosis,kidney disease,drug repositioning

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