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BACE1 Inhibition Using 2'-OMePS Steric Blocking Antisense Oligonucleotides

Authors: 
Chakravarthy M, Veedu RN
Citation: 
Genes (Basel). 2019 Sep 12;10(9):705. doi: 10.3390/genes10090705
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. [GENE TOOLS notes: different delivery, 2'-O-Me PS by lipofection, MO by electroporation]
Epub: 
Not Epub
Organism or Cell Type: 
cell culture: HEK293
Delivery Method: 
electroporation