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Open AccessArticle

BACE1 Inhibition Using 2’-OMePS Steric Blocking Antisense Oligonucleotides

1
Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, Australia
2
Perron Institute for Neurological and Translational Science, Perth 6150, Australia
*
Author to whom correspondence should be addressed.
Genes 2019, 10(9), 705; https://doi.org/10.3390/genes10090705
Received: 20 August 2019 / Revised: 6 September 2019 / Accepted: 9 September 2019 / Published: 12 September 2019
(This article belongs to the Section Molecular Genetics and Genomics)
Amyloid beta-peptide is produced by the cleavage of amyloid precursor protein by two secretases, a β-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and a γ-secretase. It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer’s disease may be beneficial in preventing cognitive decline. In this study, we report the development of a novel antisense oligonucleotide (AO) that could efficiently downregulate the BACE1 transcript and partially inhibit BACE1 protein. We designed and synthesised a range of 2’-OMethyl-modified antisense oligonucleotides with a phosphorothioate backbone across various exons of the BACE1 transcript, of which AO2, targeting exon 2, efficiently downregulated BACE1 RNA expression by 90%. The sequence of AO2 was later synthesised with a phosphorodiamidate morpholino chemistry, which was found to be not as efficient at downregulating BACE1 expression as the 2’-OMethyl antisense oligonucleotides with a phosphorothioate backbone variant. AO2 also reduced BACE1 protein levels by 45%. In line with our results, we firmly believe that AO2 could be used as a potential preventative therapeutic strategy for Alzheimer’s disease. View Full-Text
Keywords: chemically-modified oligonucleotides; antisense oligonucleotides; Alzheimer’s disease chemically-modified oligonucleotides; antisense oligonucleotides; Alzheimer’s disease
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Chakravarthy, M.; Veedu, R.N. BACE1 Inhibition Using 2’-OMePS Steric Blocking Antisense Oligonucleotides. Genes 2019, 10, 705.

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