JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

Nystrom, Sarah; Li, Guojie; Datta, Somenath; Soldano, Karen; Silas, Daniel; Weins, Astrid; Hall, Gentzon; Thomas, David B.; Olabisi, Opeyemi

doi:10.1172/jci.insight.157432

Cited by 35 publications

(28 citation statements)

References 46 publications

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“…Alternative approaches have been proposed for APOL1 inhibition including the use of antisense oligonucleotides 26 and JAK-STAT inhibition with baricitinib (NCT05237388) for cytokine-induced APOL1 -mediated podocytopathy. 27 …”

Section: Current Treatment Guidelinesmentioning

confidence: 99%

Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis

Cos

Meliambro

2023

Kidney International Reports

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Section: Current Treatment Guidelinesmentioning

confidence: 99%

Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis

Cos

Meliambro

2023

Kidney International Reports

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“…The JAK/STAT signalling components like JAK1‐3 and STAT1‐6 have been associated with various roles in immune responses to SARS‐CoV2, leading to an increase in IL‐2, IL‐4, IL‐6, IL‐12 signalling, Th (T‐helper) 1, Th2, Treg cell and Th9, Th 17 cell differentiation and NK activation. Blocking JAK/STAT pathway could prevent interleukin‐mediated hyper inflammation 12 as well as interfere with several SARS‐CoV‐2 pathophysiological mechanisms 25,26 …”

Section: Discussionmentioning

confidence: 99%

“…Blocking JAK/STAT pathway could prevent interleukinmediated hyper inflammation 12 as well as interfere with several SARS-CoV-2 pathophysiological mechanisms. 25,26 These observations triggered the design of multiple trials investigating the efficacy and safety of baricitinib, showing promising results even in particularly fragile subpopulations, 27,28 and further investigations are ongoing. 29 Within the JAK family, JAK1 is the dominant kinase activated by IL-6 in vivo, 30,31 and since tofacitinib is selective for JAK3 and JAK1, 32 the use of this JAK inhibitor appears to be another promising therapeutic intervention.…”

Section: Adverse Eventsmentioning

confidence: 99%

Early administration of tofacitinib in COVID‐19 pneumonitis: An open randomised controlled trial

Ferrarini

Vacca²,

Solimando

et al. 2022

Eur J Clin Investigation

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Background Controversies on sub‐populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID‐19. Objectives We designed a multicentre open‐label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID‐19 pneumonitis. Methods Patients admitted to three Italian hospitals affected by COVID‐19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission. Results A total of 116 patients were randomised; 49 in the experimental arm completed the 14‐day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO2 > 93%, invasive mechanical ventilation or death by day 14 was 15.5%, significantly less than in the control group (20/58, 34.4%, RR 0,45, RRR −55%, NNT 5; p = .018). No differences in severe adverse effect incidence had been observed across the groups. Conclusion High‐dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.

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“…This may explain why Schistosoma infection-related GN progresses quickly to kidney failure in APOL1 carriers or in patients co-infected with HIV, HCV or HBV 8 . Type I interferons, IL-1β, IL-6 and TNF induced by SARS-CoV-2 trigger the expression of pathogenic APOL1 via JAK–STAT signalling, resulting in podocyte loss and COVID-19-associated nephropathy 51 .…”

Section: Infection-related Gnmentioning

confidence: 99%

“…A preliminary communication on a phase II clinical trial reported that treatment with the APOL1 inhibitor inaxaplin (NCT05312879) reduced the degree of proteinuria in 47.6% of patients with diverse proteinuric kidney diseases and was well tolerated. A JAK/STAT inhibitor, baricitinib, is also being explored in a phase II clinical trial (NCT05237388) for the treatment of patients with APOL1-mediated glomerular disorders 51 .…”

Section: Infection-related Gnmentioning

confidence: 99%

Glomerulonephritis: immunopathogenesis and immunotherapy

et al. 2023

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‘Glomerulonephritis’ (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.

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JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

Cited by 35 publications

References 46 publications

Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis

Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis

Early administration of tofacitinib in COVID‐19 pneumonitis: An open randomised controlled trial

Glomerulonephritis: immunopathogenesis and immunotherapy

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