Abstract: SA-PO645

Proteinuric Renal Disease Alters the Biodistribution of Antisense Oligonucleotides Allowing Reduction in Dose for Kidney Targets

Session Information

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

  • Granqvist, Anna, AstraZeneca R&D, Gothenburg, Sweden
  • William-Olsson, Lena, AstraZeneca R&D, Gothenburg, Sweden
  • Basta, Barbro, AstraZeneca R&D, Gothenburg, Sweden
  • Bell, Thomas, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Andersson, Patrik, AstraZeneca R&D, Gothenburg, Sweden
  • Soderberg, Magnus, AstraZeneca R&D, Gothenburg, Sweden
  • Anderton, Mark J, AstraZeneca R&D, Gothenburg, Sweden
  • Ahlström, Christine, AstraZeneca R&D, Gothenburg, Sweden
Background

An increasing number of oligonucleotide therapeutics are used in clinical trials today. Antisense oligonucleotides (ASOs) are predominantly taken up by the liver and kidneys, which makes them a desirable modality for the treatment of renal disease. However, there is a concern regarding potential clinical safety risks such as thrombocytopenia, injection site reactions and renal/liver toxicity at higher doses. The biodistribution of ASOs to different tissues is assisted by plasma protein binding that delays urinary excretion and it was therefore hypothesized that distribution of ASOs with phosphorothioate backbone is altered in proteinuric renal disease.

Methods

We investigated the tissue exposure and distribution of a phosphorothioate cEt gapmer ASO in the obese diabetic BTBR ob/ob mouse. This is a suitable model as it mimics key features of human diabetic nephropathy, including progressive proteinuria and glomerulopathy. Mice were subcutaneously administered weekly doses of 3, 10, 30 or 100 mg/kg ASO in saline and followed for 2-12 weeks.

Results

In all animals tissue exposure and significant knock down of the target gene in kidney was achieved (between 45-75% decreased expression, p ≤0.001).
In the diabetic BTBR ob/ob mice a shift in the distribution of ASO towards the kidney was observed in comparison to healthy mice, leading to a lower exposure in liver. Similar exposure and knock down in the kidney was achieved in the diseased animals with a 30 mg/kg dose compared with a 100 mg/kg dose in healthy animals. There were no nephrotoxic effects of the ASO treatment (determined by biomarker analysis and histology).

Conclusion

These results suggest that in a model of proteinuric renal disease similar level of kidney mRNA knockdown is observed at lower ASO dose levels compared to healthy mice. If such observations translate to patients with kidney disease, this may reduce the risk of toxicities in other organs and tissues.