PARTIAL RESCUE OF A LETHAL PHENOTYPE OF FRAGILE BONES IN TRANSGENIC MICE WITH A CHIMERIC ANTISENSE GENE DIRECTED AGAINST A MUTATED COLLAGENGENE

Previously, transgenic mice were prepared that developed a lethal phen otype of fragile bones because they expressed an internally deleted mi ni-gene for the pro alpha 1(I) chain of human type I procollagen. The shortened pro alpha 1(I) chains synthesized from the human transgene b ound to and produced degradation of normal pro alpha 1(I) chains synth esized from the normal mouse alleles. Here we assembled an antisense g ene that was similar to the internally deleted COL1A1 minigene but the 3' half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instea d of mouse sequences. Two lines of mice expressing the antisense gene were bred to two lines of transgenic mice expressing the mini-gene. In mice that inherited both genes, the incidence of the lethal fragile b one phenotype was reduced from 92% to 27%. The effects of the antisens e gene were directly demonstrated by an increase in the ratio of norma l mouse pro alpha 1(I) chains to human mini-pro alpha 1(I) chains in t issues from mice that inherited both genes and had a normal phenotype. The results raise the possibility that chimeric gene constructs that contain intron sequences and in which only the second half of a gene i s inverted may be particularly effective as antisense genes.