Late onset Pompe disease: Rescue of acid alpha-glucosidase expression by splice modification

A deficiency of the enzyme acid alpha‐glucosidase leads to Pompe disease, also known as glycogen storage disease II (GSDII). It is an autosomal recessive disorder, and affected individuals are unable to degrade glycogen stored within lysosomes, leading to an accumulation of glycogen in tissue. Clinically, GSDII may manifest with a broad spectrum of severity, ranging from severe/infantile to a milder late onset adult form. The most common GAA mutation associated with the latter form is IVS1‐13T>G, found in over two thirds of adult onset GSDII patients. The consequence of this mutation is production of a non-functional GAA transcript because exon 2 is excluded during pre-RNA splicing. Current enzyme replacement therapy for Pompe disease has drawbacks, including immune reaction and poor delivery to target tissues. Therefore an efficient alternative therapy is needed. We sought to restore inclusion of GAA exon 2 using splice switching antisense oligomers (AO) directed at splice silencer elements to promote recognition and retention of exon 2 in the mature GAA mRNA, thereby restoring enzyme function. Screen of the best AO sequences that promote exon 2 inclusion in GAA transcript was carried out in fibroblasts derived from adult Pompe patients. Phosphorodiamidate morpholino oligomers (PMOs) were transfected into patient cells and RT‐PCR and acid‐alpha‐glucosidase enzyme activitywere performed. Several PMOs showed an increase in full‐length amplicon and increase inGAAactivity. These results show thatPMOmediatedmodification of GAA transcript could have therapeutic potential for a large portion of adult onset Pompe patients.