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Evaluation of the Renal Effects of an Antisense Phosphorothioate Oligodeoxynucleotide in Monkeys
David K. Monteith
Isis Pharmaceuticals, Carlsbad, California 92008
Michelle J. Horner
Sierra Biomedical, Inc., Sparks, Nevada 89431
Nancy A. Gillett
Sierra Biomedical, Inc., Sparks, Nevada 89431
Madeline Butler
Isis Pharmaceuticals, Carlsbad, California 92008
Richard Geary
Isis Pharmaceuticals, Carlsbad, California 92008
Todd Burckin
Isis Pharmaceuticals, Carlsbad, California 92008
Tanya Ushiro-Watanabe
Isis Pharmaceuticals, Carlsbad, California 92008
Arthur A. Levin
Isis Pharmaceuticals, Carlsbad, California 92008, alevin@ isisph.com.
Antisense phosphorothioate oligodeoxynucleotides are therapeutic agents that provide target specificity resulting from Watson-Crick base pairing. However, there are nonspecific effects that in some instances result in toxicity. These compounds accumulate in the kidney and induce renal proximal tubular degeneration at high doses. The relationship between accumulation of phosphorothioate oligodeoxynucleotides in the kidney, indicators of renal toxicity, and histomorphology were investigated in rhesus monkeys. Monkeys received vehicle or an escalating dose regimen of 3, 10, 40, and 80 mg/kg of ISIS 2105 and were then evaluated for changes in clinical pathology indices, urinalysis parameters, and renal histopathology. Urinalysis revealed an increase in protein levels and a slight increase in blood content following the third 40 mg/kg dose and continuing through the 80 mg/kg doses, whereas other urinary markers of renal toxicity were unchanged. Creatinine clearance was slightly decreased in monkeys during the 80 mg/kg dose cycle. Granulation in the cytoplasm of proximal tubular epithelial cells was evident by microscopic examination of kidney and was present at all doses examined and increased with dose. Immunohistochemical staining localized the oligodeoxynucleotide within these granules. Histopathologic changes consisting of minimal to moderate tubular degeneration were present only at the higher doses of 40 and 80 mg/kg and at high tissue concentrations, and these changes occurred concurrent with functional alterations, whereas lower doses ( 10 mg/kg) did not affect a pathologic or functional change.
Key Words: Kidney toxicity • nephrotoxicity • oligonucleotide • primate renal function
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Toxicologic Pathology, Vol. 27, No. 3,
307-317 (1999)
DOI: 10.1177/019262339902700306
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