Description
African Americans develop end-stage renal disease at a higher rate compared to European Americans due to two polymorphisms (G1 and G2 risk variants) in the apolipoprotein L1 (APOL1) gene that are common in people of African ancestry. Not all homozygous risk allele carriers, however, develop renal disease suggesting that modifying factors (second hits) are required. Although the compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease (CKD), drug discovery efforts have been greatly hindered by the fact that APOL1 expression is limited to humans and select nonhuman primates. We describe a 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 nave genomic APOL1 transgenic mice did not exhibit a renal disease phenotype, a single administration of IFN was sufficient to robustly induce proteinuria only in APOL1 G1 transgenic mice, despite inducing kidney APOL1 expression in both G0 and G1 mice, serving as a clinically-relevant second hit. We also report on the discovery of the first APOL1 inhibitor, IONIS-APOL1Rx, a Generation 2.5 antisense oligonucleotide (ASO) targeting APOL1 mRNA. Treatment of APOL1 G1 mice with IONIS-APOL1Rx prior to IFN challenge robustly and dose-dependently inhibited kidney and liver APOL1 expression and protected against IFN-induced proteinuria, indicating that the disease-relevant cell types are sensitive to ASO treatment. Collectively, these data suggest that IONIS-APOL1Rx may be an effective therapeutic for APOL1 nephropathies and warrants further development.
Overall Design
APOL1 G0 and G1 transgenic mice were dosed with PBS (vehicle), 50 mg/kg control ASO (non-targeting ASO of the same chemistry as targeting ASO) or 50 mg/kg APOL1 ASO once/week for 4 weeks. One day after the last ASO dose, cohorts were divided and half were challenged with PBS and half were challenged with IFNgamma. Kidney and Liver tissues were harvested 48 hours after challenge for analysis. N=3-4 per group.
Curator
hy_li