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Abstract: SA-PO631

The Distribution Profile of Anti-Sense Oligonucleotides Indicates That Proximal Tubular Targets Should Be Prioritized in Renal Disease

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Granqvist, Anna, AstraZeneca, Molndal, Sweden
  • William-Olsson, Lena, AstraZeneca, Molndal, Sweden
  • Basta, Barbro, Astrazeneca, Mondal, Sweden
  • Ericson, Charlotte, AstraZeneca, Molndal, Sweden
  • Tonelius, Pernilla, AstraZeneca, Molndal, Sweden
  • Wåhlander, Åsa, AstraZeneca, Molndal, Sweden
  • Bell, Thomas, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Andersson, Patrik, AstraZeneca, Molndal, Sweden
  • Soderberg, Magnus, AstraZeneca, Molndal, Sweden
  • Unwin, Robert J., University College London Medical School, London, United Kingdom
  • Anderton, Mark J., AstraZeneca, Molndal, Sweden
  • Ahlström, Christine, AstraZeneca, Molndal, Sweden
Background


Antisense oligonucleotides (ASOs) are predominantly taken up by the liver and kidneys, which makes them a potentially attractive modality for the treatment of renal disease. However, it is not clear to what extent ASOs reach the different compartments of the kidney.
The biodistribution of ASOs is dependent on plasma protein binding, which delays urinary excretion, but may also facilitate uptake into proximal tubular cells (PTCs).

Methods


We investigated the tissue exposure and distribution of a phosphorothioate cEt gapmer ASO in three different renal disease models: the diabetic BTBRob/ob, the 5/6 nephrectomy and the adenine diet mouse models. Mice were subcutaneously administered weekly doses of 3, 10 or 30 mg/kg ASO and followed for between 2 and 12 weeks.

Results

In all treated animals, renal tissue ASO exposure and significant knockdown of the target gene were achieved. Detailed analysis of the ASO distribution and knockdown revealed that the primary site of action is the PTCs, whereas knockdown in the glomerular compartment required higher doses. Uptake of ASOs in distal tubules was only detected in the adenine model in which PTCs were severely injured.

Conclusion

These results indicate that ASOs can primarily be used for treatment targets in PTCs, while targets in the distal tubule will require facilitated delivery for efficient knockdown.

Funding

  • Commercial Support