Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys.
The toxicity of ISIS 2302, a phosphorothioate oligonucleotide with antisense activity against human ICAM-1 mRNA, was investigated in cynomolgus monkeys (young adult). The oligonucleotide was administered by slow bolus injection every other day for 28 days (14 doses) at dose levels of 0, 2, 10, and 50 mg/kg/injection. The basic group size consisted of three male and three female monkeys which were sacrificed 2 days after the last dose. An additional 2 monkeys/sex in the vehicle control and 50 mg/kg dose groups remained on study for a 28-day treatment-free period. No treatment-related deaths occurred during this study, however, one monkey in the 10 mg/kg dose group was markedly lethargic after the first dose. Other clinical observations included periocular swelling (> or = 10 mg/kg) on the first day of the study, and bruising in all dose groups throughout the study. Bruising was associated with a dose-dependent prolongation of clotting times, particularly activated partial thromboplastin times (APTT), that was transient in nature. Bruises occurred around site of intravenous dosing or blood collection, and were manifested as subcutaneous hemorrhages upon microscopic evaluation. There were no corresponding alterations in hematology parameters including RBC or platelet counts. Other treatment-related microscopic alterations noted were intracytoplasmic eosinophilic granules and vacuolation in proximal tubular epithelial cells at 10 and 50 mg/kg, with free RBC in renal proximal tubular lumens at 50 mg/kg. Serum chemistry parameters including BUN and creatinine levels were normal in all dose groups and there were no notable alterations in urinalysis parameters. Granules and vacuolations in kidneys were reversed following a 4-week treatment free period. In general, 10 and 50 mg/kg ISIS 2302 produced dose-dependent changes in clotting times and the kidney that were reversible, while 2 mg/kg ISIS 2302 produced no remarkable alterations.
Henry
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Department of Toxicology, Isis Pharmaceuticals Inc., Carlsbad, CA 92008, USA. shenry@isisph.com
Bolte
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Auletta
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Kornbrust
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D000818:Animals; D001774:Blood Chemical Analysis; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000633:toxicity*; D010314:Partial Thromboplastin Time; D054735:Phosphorothioate Oligonucleotides; D010976:Platelet Count / Q000187:drug effects; D011517:Prothrombin Time; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013873:Thionucleotides / Q000008:administration & dosage / Q000633:toxicity*
D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D003404:Creatinine; C089753:alicaforsen