Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production.

Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of Aβ. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of Aβ. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce Aβ peptide and that promoting the production of this isoform with an SSO can reduce Aβ in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Aβ as a potential approach for treating AD.