Journal article
BACE1 inhibition using 2’-OMePS steric blocking antisense oligonucleotides
Genes, Vol.10(9)
2019
Abstract
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
Details
- Title
- BACE1 inhibition using 2’-OMePS steric blocking antisense oligonucleotides
- Authors/Creators
- M. Chakravarthy (Author/Creator) - Murdoch UniversityR.N. Veedu (Author/Creator) - Murdoch University
- Publication Details
- Genes, Vol.10(9)
- Publisher
- MDPI
- Identifiers
- 991005544205707891
- Copyright
- © 2019 by the authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.57 Alzheimer's Mechanisms
- Web Of Science research areas
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics