Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides

Abstract

Apolipoprotein E receptor 2 (ApoER2) is an apolipoprotein E receptor involved in long‐term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for the receptor in the disease is not clear. ApoER2 signaling requires amino acids encoded by alternatively spliced exon 19. Here, we report that the balance of ApoER2 exon 19 splicing is deregulated in postmortem brain tissue from AD patients and in a transgenic mouse model of AD. To test the role of deregulated ApoER2 splicing in AD, we designed an antisense oligonucleotide (ASO) that increases exon 19 splicing. Treatment of AD mice with a single dose of ASO corrected ApoER2 splicing for up to 6 months and improved synaptic function and learning and memory. These results reveal an association between ApoER2 isoform expression and AD, and provide preclinical evidence for the utility of ASOs as a therapeutic approach to mitigate Alzheimer's disease symptoms by improving ApoER2 exon 19 splicing.

Antisense oligonucleotides delivered to the amniotic cavityin uteromodulate gene expression in the postnatal mouse

“…ASO-C, (5′-TTAGTTTAATCACGCTCG-3′) and ASO-Ush (ASO-29) (5′- AGCTGATCATATTCTACC-3′) have a fully-modified phosphorothioate backbone with 2′-MOE modifications at all positions as previously described (28,29). …”

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

“…Specifically, inclusion of exon 19 in the ApoER2 gene enables interaction with NMDA receptors to facilitate synaptic function and plasticity (Vollmer and Krieg, 2009). This splicing event at exon 19 appears deregulated in human AD and in aged mice (Hinrich et al, 2016). Restoration of full-length ApoER2 via ASO-mediated splicing correction afforded improvements in synaptic function and cognitive behavior in APP mutant mice (TgCRND8) (Hinrich et al, 2016).…”

Splice-switching antisense oligonucleotides as therapeutic drugs

“…The effects of a single injection of SSOs on splicing and/or disease have been found to last for up to a year in some tissues when delivered peripherally (40,41) or centrally (32,41,42). This persistent effect of SSOs suggests injections could be minimized.…”