Antisense oligonucleotides promote exon inclusion and correct the common c.-32-13T > G (IVS1) GAA splicing variant in iPS-derived skeletal muscle cells from Pompe patients

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The most common variant causing Pompe disease is c.-32-13T > G (IVS1) in the acid α-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild type splicing, leading to a childhood/adult onset phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs) to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 snRNA-based AONs.

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