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Antisense oligonucleotide treatment ameliorates IFN-γ–induced proteinuria in APOL1-transgenic mice
Mariam Aghajan, … , Maria Chiara Magnone, Shuling Guo
Mariam Aghajan, … , Maria Chiara Magnone, Shuling Guo
Published June 20, 2019
Citation Information: JCI Insight. 2019;4(12):e126124. https://doi.org/10.1172/jci.insight.126124.
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Research Article Nephrology Therapeutics

Antisense oligonucleotide treatment ameliorates IFN-γ–induced proteinuria in APOL1-transgenic mice

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Abstract

African Americans develop end-stage renal disease at a higher rate compared with European Americans due to 2 polymorphisms (G1 and G2 risk variants) in the apolipoprotein L1 (APOL1) gene common in people of African ancestry. Although this compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease, drug discovery efforts have been greatly hindered by the fact that APOL1 expression is lacking in rodents. Here, we describe a potentially novel physiologically relevant genomic mouse model of APOL1-associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. While naive APOL1-transgenic mice did not exhibit a renal disease phenotype, administration of IFN-γ was sufficient to robustly induce proteinuria only in APOL1 G1 mice, despite inducing kidney APOL1 expression in both G0 and G1 mice, serving as a clinically relevant “second hit.” Treatment of APOL1 G1 mice with IONIS-APOL1Rx, an antisense oligonucleotide (ASO) targeting APOL1 mRNA, prior to IFN-γ challenge robustly and dose-dependently inhibited kidney and liver APOL1 expression and protected against IFN-γ–induced proteinuria, indicating that the disease-relevant cell types are sensitive to ASO treatment. Therefore, IONIS-APOL1Rx may be an effective therapeutic for APOL1 nephropathies and warrants further development.

Authors

Mariam Aghajan, Sheri L. Booten, Magnus Althage, Christopher E. Hart, Anette Ericsson, Ingela Maxvall, Joseph Ochaba, Angela Menschik-Lundin, Judith Hartleib, Steven Kuntz, Danielle Gattis, Christine Ahlström, Andrew T. Watt, Jeffery A. Engelhardt, Brett P. Monia, Maria Chiara Magnone, Shuling Guo

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Figure 8

Hepatocyte-targeted IONIS-APOL1Rx provides incomplete protection against IFN-γ–induced proteinuria.

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Hepatocyte-targeted IONIS-APOL1Rx provides incomplete protection against...
Female APOL1 G1–transgenic mice (n = 4) were treated with IONIS-APOL1Rx, hepatocyte-targeted IONIS-APOL1Rx, or control ASO 1 time per week for 4 weeks and challenged with a single dose of IFN-γ (1.125 × 107 U/kg) or vehicle (PBS). Study endpoints were evaluated 48 hours after IFN-γ challenge. (A) Kidney and (B) liver APOL1 expression were measured by qRT-PCR and normalized to Cyp expression. (C) Urine was collected prior to sacrifice 48 hours after IFN-γ challenge, and urinary albumin was measured by ELISA and normalized to urine creatinine. (D) Urinary shed cells were collected from PBS-challenged mice, and APOL1 expression was measured by qRT-PCR and normalized to 36B4/Rplp0 expression. All data are presented as mean ± SD. Statistics were performed (A–C) by comparing each APOL1 ASO–treated PBS- or IFN-γ–challenged group to the respective control ASO group. Two-way ANOVA with Tukey’s multiple comparisons test, *P< 0.05; ***P < 0.001.

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