Rational design of antisense oligomers to induce dystrophin exon skipping

Duchenne muscular dystrophy (DMD), one of the mostsevere neuromuscular disorders of childhood, is causedby the absence of a functional dystrophin. Antisenseoligomer (AO) induced exon skipping is being investigatedto restore functional dystrophin expression inmodels of muscular dystrophy and DMD patients. Oneof the major challenges will be in the development ofclinically relevant oligomers and exon skipping strategiesto address many different mutations. Various models,including cell-free extracts, cells transfected with artificialconstructs, or mice with a human transgene, havebeen proposed as tools to facilitate oligomer design.Despite strong sequence homology between the humanand mouse dystrophin genes, directing an oligomer tothe same motifs in both species does not always inducecomparable exon skipping. We report substantially differentlevels of exon skipping induced in normal anddystrophic human myogenic cell lines and propose thatanimal models or artificial assay systems useful in initialstudies may be of limited relevance in designing themost efficient compounds to induce targeted skippingof human dystrophin exons for therapeutic outcomes.