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Kidney Week

Abstract: FR-OR068

APOL1 Antisense Oligonucleotide Treatment Ameliorates IFNγ-Induced Proteinuria in Genomic APOL1 Transgenic Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Aghajan, Mariam, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Booten, Sheri, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Althage, Magnus, AstraZeneca, Gothenburg, Sweden
  • Ericsson, Anette E., AstraZeneca, Gothenburg, Sweden
  • Maxvall, Ingela, AstraZeneca, Gothenburg, Sweden
  • Menschik lundin, Angela, AstraZeneca, Gothenburg, Sweden
  • Ahlström, Christine, AstraZeneca, Gothenburg, Sweden
  • Ochaba, Joseph, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Gattis, Danielle, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Watt, Andy, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Engelhardt, Jeffery A., Ionis Pharmaceuticals, Carlsbad, California, United States
  • Monia, Brett P., Ionis Pharmaceuticals, Carlsbad, California, United States
  • Magnone, Maria chiara, AstraZeneca, Gothenburg, Sweden
  • Guo, Shuling, Ionis Pharmaceuticals, Carlsbad, California, United States

APOL1 risk variants (G1/G2) strongly associate with CKD in African Americans. Not all individuals homozygous for the risk variants, however, develop renal disease suggesting that a second hit is required. In this study, we sought to develop a physiologically-relevant mouse model of APOL1-associated renal disease.


We generated genomic APOL1 G0 or G1 transgenic mice via random transgenesis of a human APOL1-containing fosmid, resulting in APOL1 expression in similar tissues as that identified in humans and at similar relative levels of expression. Mice were challenged with recombinant IFNγ and APOL1 induction was measured by qRT-PCR. Proteinuria was measured by albumin ELISA and normalized using urine creatinine levels measured by a clinical chemistry analyzer.


Naïve APOL1 G1 Tg mice failed to show a differential renal phenotype compared to APOL1 G0 mice. A single dose of IFNγ, however, caused robust proteinuria only in G1 mice, despite inducing kidney APOL1 expression in both G0 and G1 mice. We identified an antisense oligonucleotide (IONIS-APOL1Rx) against APOL1 that is potent with an excellent safety profile. Administration of IONIS-APOL1Rx to G1 Tg mice prior to IFNγ challenge prevented APOL1 induction and IFNγ-induced proteinuria in a dose-dependent manner. Treatment with a hepatocyte-targeting version of IONIS-APOL1Rx, however, provided incomplete protection against IFNγ-induced proteinuria, suggesting that local expression of APOL1 in kidney is critical for pathogenesis. In search of a kidney-specific target engagement biomarker, we detected APOL1 mRNA in urinary shed cells from mice and humans and correlated its reduction to kidney APOL1 mRNA reduction in APOL1 Tg mice.


We developed a novel APOL1 transgenic mouse model that recapitulates the physiological attributes of APOL1 and exhibits a kidney phenotype in G1 mice upon IFNγ challenge. APOL1 ASO treatment in this model prevents IFNγ-induced proteinuria in G1 mice, demonstrating that the kidney disease cell type is sensitive to APOL1 ASO treatment and that IONIS-APOL1Rx may be an effective therapeutic for APOL1-associated nephropathies.


  • Commercial Support – Ionis Pharmaceuticals, AstraZeneca