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 par. 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 30S2 respectively). Male and female mice were treated prior to cohabitation, through cohabitation, gestation, delivery, and weanin-. Mice were treated with 0, 3, 6, and 12 rng/ka ISIS 2302 or ISIS 3082 bv dailv i.v. injection. Reproduchve induce-_ evaluated included estrus cycling, sperm Count and motility, fertility, litter parameters, fetal development, delivery, fecal 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 organ's, placenta, fetal and expressed milk were also measured. There were no changes in reproductive performance, litter parameters, fetal development, or postnatal development in mice treated 1 with either ISIS 2302 or ISIS 30S2. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no olligonucleotide measured in placenta, fetal tissues, or expressed milk. Neither the human nor murine-Specific antisense of ICAM-1 produced any reproductive toxicity in mice, and exposure of fetus or pups was negligible. (C) 2004 Wiley-Liss, Inc.