Aberrant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of
hepatitis. We have explored the possibility that inhibition of Fas expression in mice would reduce the severity of
fulminant hepatitis. To do this, we have developed a chemically modified 2'-O-(2-methoxy)ethyl
antisense oligonucleotide (
ISIS 22023) inhibitor of mouse Fas expression. In tissue culture, this
oligonucleotide induced a reduction in Fas
mRNA expression that was both concentration- and sequence-specific. In Balb/c mice, dosing with
ISIS 22023 reduced Fas
mRNA and
protein expressions in liver by 90%. The ID50 for this response was 8-10 mg kg-1 daily dosing, and the reduction was highly dependent on
oligonucleotide sequence,
oligonucleotide concentration in liver, and treatment time. Pretreatment with
ISIS 22023 completely protected mice from
fulminant hepatitis induced by agonistic Fas antibody, by a mechanism entirely consistent with an
oligonucleotide antisense mechanism of action. In addition,
oligonucleotide-mediated suppression of Fas expression reduced the severity of
acetaminophen-mediated
fulminant hepatitis, but was without effect on
concanavalin A-mediated
hepatitis. Our results demonstrate that 2'-O-(2-methoxy)ethyl containing
antisense oligonucleotides targeting Fas can exert in vivo pharmacological activity in liver, and suggest that
oligonucleotide inhibitors of Fas may be useful in the treatment of human
liver disease.