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Transport of phosphorothioate oligonucleotides in kidney: implications for molecular therapy

J Rappaport1, B Hanss, J B Kopp

  • 1Division of Nephrology, Mt. Sinai Medical Center, New York, New York, USA.

Kidney International
|May 1, 1995
PubMed

Insights

Systemic administration of phosphorothioated antisense oligonucleotides (ASOs) shows the kidney is a key site for DNA transport. Renal epithelial cells efficiently uptake ASOs, suggesting potential for targeted therapy and toxicity.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Nephrology

Background:

  • Systemic administration of phosphorothioated antisense oligonucleotides (ASOs) is effective for gene expression control.
  • Previous studies indicated hepatic and renal accumulation of systemically administered oligonucleotides.
  • The kidney's role in free DNA transport requires further investigation.

Purpose of the Study:

  • To investigate the kidney as a potential site for free DNA transport.
  • To determine the renal handling and cellular uptake of systemically administered ASOs.

Main Methods:

  • Administration of [32P]-phosphorothioate oligonucleotides (20-mers) in rats.
  • Measurement of oligonucleotide excretion in urine and plasma clearance.
  • Autoradiography of renal tissue to localize ASOs.
  • Analysis of brush border membrane preparations for oligonucleotide binding proteins using gel mobility shift and UV cross-linking assays.

Main Results:

  • Oligonucleotides were excreted in urine but cleared at 30% of glomerular filtration rate.
  • Plasma clearance of the label was rapid (t1/2 ≈ 5 min), while urinary excretion was slower (t1/2 ≈ 28 min).
  • Autoradiography revealed ASOs within Bowman's capsule and proximal tubules, associated with brush border membranes and tubular epithelial cells.
  • Oligonucleotide binding proteins were identified in rat kidney brush border membranes.

Conclusions:

  • Renal epithelial cells efficiently take up phosphorothioated oligonucleotides without significant degradation.
  • The kidney is a potential target site for site-directed antisense therapy.
  • The kidney may also be a site for antisense oligonucleotide-induced toxicity.

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