Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to
protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching
antisense oligonucleotides offer a potential therapeutic
solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping
antisense oligonucleotide that has a
therapeutic effect in a mouse model of CLN3
Batten disease, a fatal pediatric
lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced
isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that
antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3
Batten disease. This model highlights how
protein engineering through RNA splicing modulation can be an effective therapeutic approach.