Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression
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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/11/6/667 |
| _version_ | 1797564819570688000 |
|---|---|
| author | Madhuri Chakravarthy Suxiang Chen Tao Wang Rakesh N. Veedu |
| author_facet | Madhuri Chakravarthy Suxiang Chen Tao Wang Rakesh N. Veedu |
| author_sort | Madhuri Chakravarthy |
| collection | DOAJ |
| description | 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 <i>MAPT</i> 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 <i>MAPT</i> 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. |
| first_indexed | 2024-03-10T19:02:23Z |
| format | Article |
| id | doaj.art-95063f3222f44282b76548a6bf661b1c |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T19:02:23Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-95063f3222f44282b76548a6bf661b1c2023-11-20T04:19:23ZengMDPI AGGenes2073-44252020-06-0111666710.3390/genes11060667Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene ExpressionMadhuri Chakravarthy0Suxiang Chen1Tao Wang2Rakesh N. Veedu3Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaThe 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 <i>MAPT</i> 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 <i>MAPT</i> 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.https://www.mdpi.com/2073-4425/11/6/667Alzheimer’s disease<i>MAPT</i>tauDNAzymesantisense oligonucleotides |
| spellingShingle | Madhuri Chakravarthy Suxiang Chen Tao Wang Rakesh N. Veedu Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression Genes Alzheimer’s disease <i>MAPT</i> tau DNAzymes antisense oligonucleotides |
| title | Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression |
| title_full | Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression |
| title_fullStr | Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression |
| title_full_unstemmed | Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression |
| title_short | Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human <i>MAPT</i> Gene Expression |
| title_sort | development of novel chemically modified nucleic acid molecules for efficient inhibition of human i mapt i gene expression |
| topic | Alzheimer’s disease <i>MAPT</i> tau DNAzymes antisense oligonucleotides |
| url | https://www.mdpi.com/2073-4425/11/6/667 |
| work_keys_str_mv | AT madhurichakravarthy developmentofnovelchemicallymodifiednucleicacidmoleculesforefficientinhibitionofhumanimaptigeneexpression AT suxiangchen developmentofnovelchemicallymodifiednucleicacidmoleculesforefficientinhibitionofhumanimaptigeneexpression AT taowang developmentofnovelchemicallymodifiednucleicacidmoleculesforefficientinhibitionofhumanimaptigeneexpression AT rakeshnveedu developmentofnovelchemicallymodifiednucleicacidmoleculesforefficientinhibitionofhumanimaptigeneexpression |