Effects of human and murine antisense oligonucleotide inhibitors of ICAM-1 on reproductive performance, fetal development, and post-natal development in mice.
The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. Since antisense compounds are often specific to the species in which they are intended to work, both the human and murine active ICAM-1 inhibitors were tested (ISIS 2302 and ISIS 3082, respectively). Male and female mice were treated prior to cohabitation, through cohabitation, gestation, delivery, and weaning. Mice were treated with 0, 3, 6, and 12 mg/kg ISIS 2302 or ISIS 3082 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, sperm count and motility, fertility, litter parameters, fetal development, delivery, fetal body weight, lactation, and weaning. Behavioral assessment and reproductive capacity of the F1 generation mice was assessed on selected animals. Concentrations of oligonucleotide in selected maternal target organs, placenta, fetal tissues, and expressed milk were also measured. There were no changes in reproductive performance, litter parameters, fetal development, or postnatal development in mice treated with either ISIS 2302 or ISIS 3082. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta, fetal tissues, or expressed milk. Neither the human nor murine-specific antisense inhibitor of ICAM-1 produced any reproductive toxicity in mice, and exposure of fetus or pups was negligible.
Henry
Scott P
SP
Isis Pharmaceuticals, Carlsbad, CA 92008, USA. Shenry@isisph.com
Denny
Kevin H
KH
Templin
Mike V
MV
Yu
Rosie Z
RZ
Levin
Arthur A
AA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004971:Estrus / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007774:Lactation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020319:Oligodeoxyribonucleotides, Antisense / Q000633:toxicity*; D054735:Phosphorothioate Oligonucleotides; D012098:Reproduction / Q000187:drug effects*; D013081:Sperm Motility / Q000187:drug effects; D013873:Thionucleotides / Q000633:toxicity*
D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; C089753:alicaforsen