Exon skipping uses antisense oligonucleotides (ASOs) to alter transcript splicing for the purpose of rescuing or modulating protein expression. In this issue of the JCI, Lee and colleagues developed and evaluated an ASO-dependent method for treating certain molecularly defined diseases associated with alterations in lamin A/C (LMNA) splicing. Exon skipping by ASOs is gaining traction as a therapeutic strategy, and the use of ASOs is now being applied to bypass mutations and generate modified but functional proteins for an array of genetic disorders.
(A) Lamin A and lamin C are produced from a single gene through alternative splicing. (B) Laminopathies result from mutations that alter lamin A processing. ASOs were designed to target exon 11 to shift the ratio of lamin A–encoding mRNA to lamin C–encoding mRNA. This strategy would treat laminopathies due to mutations in exon 11 and 12. Exons 1–12 are shown.