Antisense therapy corrects nonsense mutation by exon skipping.
Extract: Antisense technology is based on the principle that antisense oligonucleotides (AO) can specifically alter gene expression and the pattern of splicing at the RNA level. The first application of such technology 25 years ago was for knockdown of targeted viral gene expression, which was achieved by targeting mRNA with AO to block the viral gene translation or induce its degradation. Such strategies have now been developed as powerful tools for the functional analysis of targeted genes in the laboratory and are suggested to be of great therapeutic potential against diseases from viral infections to cancers. More recently, antisense technologies have been devised for interference with gene splicing. Such applications target pre-mRNA rather than mRNA and was first established in vitro for correction of altered exon splicing in beta-thalassemia. Mutations in the beta-globin gene activate a cryptic site in the pre-mRNA and as a result the intronic sequences are spliced into the mRNA. This causes disruption of normal protein synthesis. Kole and his colleagues designed specific AO to the cryptic splicing site and successfully blocked its recognition and restored the normal splicing pattern of the gene. The use of AO for selective exon skipping was quickly explored by several laboratories to correct gene mutations for the treatment of Duchenne muscular dystrophy (DMD).
Lu
Qi Long
QL
Muscle Cell Biology, MRC Clinical Science Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Partridge
Terence A
TA