Abstract
The hyperphosphorylation of the microtubule-associated protein tau (MAPT) has been implicated in various neurological diseases, including Alzheimer’s disease. It has been hypothesized that the reduction of MAPT would result in depolymerizing neurofibrillary tangles and could be a potential strategy for the treatment of Alzheimer’s disease and other tauopathies. In this study, we report the development of novel DNAzymes and splice-modulating antisense oligonucleotides (AOs) for the efficient inhibition of MAPT. We designed and synthesized a range of DNAzymes and 2ʹ-O-methyl (2’-OMe)-modified AOs on a phosphorothioate (PS) backbone targeting various exons across the MAPT gene transcript. Our results demonstrated that RNV563, an arm-loop-arm-type DNAzyme targeting exon 13, and an AO candidate AO4, targeting exon 4, efficiently downregulated MAPT RNA expression by 58% and 96%, respectively. In addition, AO4 also reduced the MAPT protein level by 74%. In line with our results, we believe that AO4 could be used as a potential therapeutic molecule for Alzheimer’s disease and other tauopathies.
Highlights
Synthetic nucleic acid-based technologies offer great promise for the development of precision therapeutics for the treatment of various diseases
Inspired by the rapid progress in the translation of nucleic acid drugs in recent years, we envisioned the development of novel nucleic acid molecules for targeting the microtubule-associated protein tau (MAPT), which is a protein that belongs to the microtubule-associated protein family [3]
The catalytic activities of all the designed DNAzymes against MAPT mRNA were screened in SH-SY5Y neuroblastoma cells by transfecting at two different concentrations (400 and 50 nM) for 24 h
Summary
Synthetic nucleic acid-based technologies offer great promise for the development of precision therapeutics for the treatment of various diseases. Inspired by the rapid progress in the translation of nucleic acid drugs in recent years, we envisioned the development of novel nucleic acid molecules for targeting the microtubule-associated protein tau (MAPT), which is a protein that belongs to the microtubule-associated protein family [3]. There are six isoforms of tau found in the adult brain produced through alternative splicing of the MAPT pre-mRNA [4,5] (Figure S9, Supplementary Material). Three of the isoforms have a three-repeat segment in the microtubule binding domain, while the other three have a four-repeat segment in the microtubule binding domain, and both groups are found in equal amounts in the adult brain [4,5]
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