Characterization of the Activity and Distribution of a 2'-O-Methoxyethyl-Modified Antisense Oligonucleotide in Models of Acute and Chronic Kidney Disease

Abstract

To determine if the pharmacokinetics and pharmacodynamics of gapmer antisense oligonucleotides (ASOs), containing phosphorothioate backbones and 2'-O-methoxyethyl RNA modifications (2'-MOE ASOs), can be altered by renal disease, a series of experiments were performed in models of chronic kidney disease (CKD) and acute kidney injury (AKI). In an adenine diet model of CKD, 2'-MOE ASO activity in the whole kidney was preserved and the reduction in target RNA was sustained for 2-4 weeks postdose. Additionally, 2'-MOE ASO distribution within the kidney was altered in mice with CKD, in that ASO delivery to cortical regions with tubular damage was reduced while distribution to the medulla was increased. Finally, the concentration of 2'-MOE ASO in liver of mice with CKD was elevated relative to mice without CKD, indicating a reduction in renal function and ASO excretion can potentially alter the systemic delivery of 2'-MOE ASOs. These data were generally reproduced in an aristolochic acid model of AKI, with the exception that 2'-MOE ASO activity in the whole kidney was slightly reduced with acute injury. The results from these studies have important implications for the development of 2'-MOE ASO therapeutics as both renal and extrarenal 2'-MOE ASO pharmacokinetics and pharmacodynamics may be altered in patients with renal disease. Importantly, the underlying mechanisms that alter 2'-MOE ASO distribution in the context of kidney disease warrant further examination.

Keywords: kidney; pharmacodynamic; pharmacokinetic.