ORCID Profile
0000-0003-1881-8153
Current Organisations
ProGenis Pharmaceuticals
,
Murdoch University
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Publisher: Wiley
Date: 22-10-2021
Abstract: We have found that antisense oligonucleotides and siRNA molecules modified with repeat structures of disulfide units can be directly introduced into the cytoplasm and exhibit a suppressive effect on gene expression. In this study, we analyzed the mechanism of cellular uptake of these membrane‐permeable oligonucleotides (MPONs). Time‐course analysis by confocal microscopy showed that the uptake of MPONs from the plasma membrane to the cytoplasm reached 50 % of the total uptake in about 5 min. In addition, analysis of the plasma membrane proteins to which MPONs bind, identified several proteins, including voltage‐dependent anion channel. Next, we analyzed the behavior of MPONs in the cell and found them to be abundant in the nucleus as early as 24 h after addition with the amount increasing further after 48 and 72 h. The amount of MPONs was 2.5‐fold higher than that of unmodified oligonucleotides in the nucleus after 72 h. We also designed antisense oligonucleotides and evaluated the effect of MPONs on mRNA exon skipping using DMD model cells MPONs caused exon skipping with 69 % efficiency after 72 h, which was three times higher than the rate of the control. In summary, the high capacity for intracytoplasmic and nuclear translocation of MPONs is expected to be useful for therapeutic strategies targeting exon skipping.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-08-2022
Abstract: Recent advances in drug development have seen numerous successful clinical translations using synthetic antisense oligonucleotides (ASOs). However, major obstacles, such as challenging large-scale production, toxicity, localization of oligonucleotides in specific cellular compartments or tissues, and the high cost of treatment, need to be addressed. Thiomorpholino oligonucleotides (TMOs) are a recently developed novel nucleic acid analog that may potentially address these issues. TMOs are composed of a morpholino nucleoside joined by thiophosphoramidate internucleotide linkages. Unlike phosphorodiamidate morpholino oligomers (PMOs) that are currently used in various splice-switching ASO drugs, TMOs can be synthesized using solid-phase oligonucleotide synthesis methodologies. In this study, we synthesized various TMOs and evaluated their efficacy to induce exon skipping in a Duchenne muscular dystrophy (DMD) in vitro model using H2K mdx mouse myotubes. Our experiments demonstrated that TMOs can efficiently internalize and induce excellent exon 23 skipping potency compared with a conventional PMO control and other widely used nucleotide analogs, such as 2′-O-methyl and 2′-O-methoxyethyl ASOs. Notably, TMOs performed well at low concentrations (5–20 nM). Therefore, the dosages can be minimized, which may improve the drug safety profile. Based on the present study, we propose that TMOs represent a new, promising class of nucleic acid analogs for future oligonucleotide therapeutic development.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA22346J
Abstract: We have investigated the applicability of twisted intercalating nucleic acids (TINA)-modified antisense oligonucleotides (AOs) in exon skipping. We found that TINA-modified AOs induced exon skipping.
Publisher: MDPI AG
Date: 19-10-2017
Publisher: Elsevier BV
Date: 03-2019
Publisher: Informa Healthcare
Date: 15-12-2015
Publisher: Elsevier BV
Date: 12-2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8RA06050A
Abstract: We investigated the potential of UNA-modified primers for mismatch recognition capabilities using enzymatic polymerisation approach. Efficient allele-specific discrimination was achieved with the UNA-modified primers unlike the DNA primers.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
DOI: 10.1038/S41598-018-22902-9
Abstract: Despite advancements in the development of high generation cationic-dendrimer systems for delivery of nucleic acid-based therapeutics, commercially available chemical agents suffer from major drawbacks such as cytotoxicity while being laborious and costly to synthesize. To overcome the aforementioned limitations, low-generation cationic peptide asymmetric dendrimers with side arm lipid (cholic and decanoic acid) conjugation were designed, synthesized and systematically screened for their ability to self-assemble into micelles using dynamic light scattering. Cytotoxicity profiling revealed that our entire asymmetric peptide dendrimer library when trialled alone, or as asymmetric dendrimer micelle-nucleic acid complexes, were non-cytotoxic across a broad concentration range. Further, the delivery efficiency of asymmetric peptide dendrimers in H-4-II-E (rat hepatoma), H2K (mdx mouse myoblast), and DAOY (human medulloblastoma) cells demonstrated that cholic acid-conjugated asymmetric dendrimers possess far superior delivery efficiency when compared to the commercial standards, Lipofectamine 2000 or Lipofectin ® .
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7RA06091B
Abstract: We investigated the potential of SNA-modified antisense oligonucleotide (AO) for exon-skipping. We found that a 20-mer SNA-AO induced efficient exon-23 skipping in the mouse dystrophin gene transcript.
Publisher: American Chemical Society (ACS)
Date: 16-07-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1RA00878A
Abstract: We evaluated the potential of 2′-modified RNA antisense oligonucleotides (ASOs) incorporated with DNA segments to induce exon skipping. Results demonstrated that ASOs with 4 or less DNA nucleotides at the 3′-end induce more efficient exon skipping compared with the control.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
DOI: 10.1038/S41598-019-42523-0
Abstract: Antisense oligonucleotide (AO)-mediated splice modulation has been established as a therapeutic approach for tackling genetic diseases. Recently, Exondys51, a drug that aims to correct splicing defects in the dystrophin gene was approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD). However, Exondys51 has relied on phosphorodiamidate morpholino oligomer (PMO) chemistry which poses challenges in the cost of production and compatibility with conventional oligonucleotide synthesis procedures. One approach to overcome this problem is to construct the AO with alternative nucleic acid chemistries using solid-phase oligonucleotide synthesis via standard phosphoramidite chemistry. 2′-Fluoro (2′-F) is a potent RNA analogue that possesses high RNA binding affinity and resistance to nuclease degradation with good safety profile, and an approved drug Macugen containing 2′-F-modified pyrimidines was approved for the treatment of age-related macular degeneration (AMD). In the present study, we investigated the scope of 2′-F nucleotides to construct mixmer and gapmer exon skipping AOs with either 2′- O -methyl (2′- O Me) or locked nucleic acid (LNA) nucleotides on a phosphorothioate (PS) backbone, and evaluated their efficacy in inducing exon-skipping in mdx mouse myotubes in vitro . Our results showed that all AOs containing 2′-F nucleotides induced efficient exon-23 skipping, with LNA/2′-F chimeras achieving better efficiency than the AOs without LNA modification. In addition, LNA/2′-F chimeric AOs demonstrated higher exonuclease stability and lower cytotoxicity than the 2′- O Me/2′-F chimeras. Overall, our findings certainly expand the scope of constructing 2′-F modified AOs in splice modulation by incorporating 2′- O Me and LNA modifications.
Publisher: MDPI AG
Date: 22-11-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CC07447B
Abstract: We have investigated the potential of anhydrohexitol, cyclohexenyl and altritol nucleic acid-modified antisense oligos in exon skipping, and found that they efficiently induced Dmd exon 23 skipping.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 12-2023
Publisher: Springer Science and Business Media LLC
Date: 16-04-2020
DOI: 10.1038/S41598-020-63706-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7RA10964D
Abstract: We investigated the potential of nucleobase-modified antisense oligonucleotides to induce exon-skipping, and found that 5-(phenyltriazol)-2′-deoxyuridine-modified antisense oligonucleotides induced efficient exon-skipping in vitro .
No related grants have been discovered for TRI BAO LE.