Antisense oligonucleotide-mediated exon skipping of @entity52164 pre-mRNA as potential therapy for XXXX .

@entity1 @entity8585 @entity8491 @entity6786 @entity52164 @entity74
@entity52164 encodes the a subunit of nicotinic acetylcholine receptors (nAChRs) and is expressed at the neuromuscular junction. Moreover, it is one of the causative genes of @entity8491 ( @entity8491 ). @entity52164 undergoes alternative splicing to produce two splice variants: P3A(-), without exon P3A, and P3A(+), with the exon P3A. Only P3A(-) forms functional @entity6786 . Aberrant alternative splicing caused by intronic or exonic point mutations in @entity1 leads to an extraordinary increase in P3A(+) and a concomitant decrease in P3A(-). Consequently this resulted in a shortage of functional receptors. Aiming to restore the imbalance between the two splice products, antisense oligonucleotides (AONs) were employed to induce exon P3A skipping. Three AON sequences were designed to sterically block the putative binding sequences for splicing factors necessary for exon recognition. Herein, we show that AON @entity8585 ' splice site of the exon was the most effective at exon skipping of the minigene with causative mutations, as well as endogenous wild-type @entity52164 . We conclude that single administration of the AON against the 5' splice site is a promising therapeutic approach for @entity1 based on the dose-dependent effect of the AON and the additive effect of combined AONs. This conclusion is favorable to @entity1 with @entity74 of uncertain etiology that arise from aberrant splicing leading to a subsequent loss of functional translation products because our findings encourage the option of AON treatment as a therapeutic for these prospectively identified diseases.
