EVALUATION OF AN ANTISENSE RNA TRANSGENE FOR INHIBITING GROWTH-HORMONE GENE-EXPRESSION IN TRANSGENIC RATS

We compared the levels of growth hormone (GH) mRNA in the pituitary, p lasma GH concentration, and altered phenotype in rats heterozygous and homozygous for an antisense RNA transgene targeted to the rat GH gene , with those in nontransgenic rats. We initially investigated whether the transgene promoter, which is connected to four copies of a thyroid hormone response element (TRE) that increases promoter activity, affe cted in vivo transgene expression in the pituitary of the transgenic r ats. Plasma GH concentration correlated negatively with T-3 injection in surgically thyroidectomized heterozygous transgenic rats. There was a reduction of about similar to 35-40% in GH mRNA levels in the pitui tary of homozygous animals compared with those in nontransgenic rats. Plasma GH concentration was significantly similar to 25-32 and similar to 29-41% lower in heterozygous and homozygous transgenic rats, respe ctively, compared with that in nontransgenic animals. Furthermore, the growth rates in homozygous transgenic rats were reduced by similar to 72-81 and similar to 51-70% compared with those of their heterozygous and nontransgenic littermates, respectively. The results of these stu dies suggested that the biological effect of GH in vivo is modulated d ose-dependently by the antisense RNA transgene. The rat GH gene can th erefore be targeted by antisense RNA produced from a transgene, as ref lected in the protein and RNA levels. (C) 1995 Wiley-Liss, Inc.