The lysosomal storage disease CNL3 Batten disease is caused by mutations in CLN3, often resulting in deletion of exons 7 and 8, leading to a premature termination codon in exon 9. Here, Centa et al. develop antisense oligonucleotides (ASOs) that induce exon skipping of exon 5 and restore the open reading frame. Exon 5-targeted ASOs exerted robust exon skipping in cell lines derived from patients with CLN3 Batten disease. ICV injection of an exon 5-targeted ASO induced stable exon skipping for up to 14 months, lowered brain accumulation of subunit c of mitochondrial ATP synthase, rescued motor deficits and increased survival in mouse disease models.
Nature Reviews Drug Discovery 19, 588 (2020)