The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice

Abstract

Introduction

Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI.

Methods

Murine models of AKI were used to assess the in vivo efficacy of opaganib including ischemia-reperfusion (IR) injury induced by either transient bilateral occlusion of renal blood flow (a moderate model) or nephrectomy followed immediately by occlusion of the contralateral kidney (a severe model) and lipopolysaccharide (LPS)-induced sepsis. Biochemical and histologic assays were used to quantify the effects of oral opaganib treatment on renal damage in these models.

Results

Opaganib suppressed the elevations of creatinine and blood urea nitrogen (BUN), as well as granulocyte infiltration into the kidneys, of mice that experienced moderate IR from transient bilateral ligation. Opaganib also markedly decreased these parameters and completely prevented mortality in the severe renal IR model. Additionally, opaganib blunted the elevations of BUN, creatinine and inflammatory cytokines following exposure to LPS.

Conclusion

The data support the hypotheses that sphingolipid metabolism is a key mediator of renal inflammatory damage following IR injury and sepsis, and that this can be suppressed by opaganib. Because opaganib has already undergone clinical testing in other diseases (cancer and Covid-19), the present studies support conducting clinical trials with this drug with surgical or septic patients at risk for AKI.

Keywords:

• opaganib
• sphingosine kinase
• sphingolipid
• acute kidney injury
• ischemia-reperfusion injury
• lipopolysaccharide
• sepsis

Abbreviations

AKI, Acute Kidney Injury; DES1, dihydroceramide desaturase 1; IR, ischemia-reperfusion; LPS, lipopolysaccharide; MPO, myeloperoxidase; PBS, phosphate-buffered saline; SK, sphingosine kinase; S1P, sphingosine 1-phosphate.

Ethical Statements

All protocols in this study were approved by the Institutional Animal Care and Use Committee (IACUC) of the Penn State University College of Medicine, in compliance with US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training, which complies with the PHS Policy on Humane Care and Use of Laboratory Animals, and the United States Department of Agriculture Animal Welfare Act guidelines.

Disclosure

Lynn W. Maines, Staci N. Keller and Charles D. Smith are current employees and own stock in Apogee Biotechnology Corporation. Apogee Biotechnology Corporation owns patent rights to opaganib (United States Patent numbers 7,338,961, 8,063,248, 8,324,237 and 8,557,800, and multiple parallel patents in other countries) that have been licensed to RedHIll Biopharma LTD. The value of these rights may be affected by the research reported in this paper. The authors report no other conflicts of interest in this work.

Additional information

Funding

All studies were funded internally by Apogee Biotechnology Corporation.