ORCID Profile
0000-0003-2192-9532
Current Organisation
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: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CC05831H
Abstract: We report a novel multifunctional hyperbranched polymer based on polyethylene glycol (PEG) as a nanomedicine platform that facilitates longitudinal and quantitative 89 Zr-PET imaging, enhancing knowledge of nanomaterial biodistribution and pharmacokinetics harmacodynamics both in vivo and ex vivo .
Publisher: MDPI AG
Date: 22-09-2019
DOI: 10.3390/IJMS20194700
Abstract: Epidermal growth factor receptor (EGFR) is associated with the progression of a wide range of cancers including breast, glioma, lung, and liver cancer. The observation that EGFR inhibition can limit the growth of EGFR positive cancers has led to the development of various EGFR inhibitors including monoclonal antibodies and small-molecule inhibitors. However, the reported toxicity and drug resistance greatly compromised the clinical outcome of such inhibitors. As a type of chemical antibodies, nucleic acid aptamer provides an opportunity to overcome the obstacles faced by current EGFR inhibitors. In this study, we have developed and investigated the therapeutic potential of a 27mer aptamer CL-4RNV616 containing 2′-O-Methyl RNA and DNA nucleotides. Our results showed that CL-4RNV616 not only displayed enhanced stability in human serum, but also effectively recognized and inhibited the proliferation of EGFR positive Huh-7 liver cancer, MDA-MB-231 breast cancer, and U87MG glioblastoma cells, with an IC50 value of 258.9 nM, 413.7 nM, and 567.9 nM, respectively. Furthermore, TUNEL apoptosis assay revealed that CL-4RNV616 efficiently induced apoptosis of cancer cells. In addition, clinical breast cancer biopsy-based immunostaining assay demonstrated that CL-4RNV616 had a comparable detection efficacy for EGFR positive breast cancer with commonly used commercial antibodies. Based on the results, we firmly believe that CL-4RNV616 could be useful in the development of targeted cancer therapeutics and diagnostics.
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: 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: American Chemical Society (ACS)
Date: 25-03-2021
Publisher: Elsevier BV
Date: 03-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CC02256A
Abstract: We have developed a novel functional nucleic acid aptamer to amyloid-β peptide 1–40 (Aβ 1–40 ) and investigated its potential to detect Aβ peptide fragments in neuropathologically confirmed Alzheimer brain hippoc us tissues s les.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2OB00304J
Abstract: No exon-skipping with antisense oligos despite high thermal stability? Consider adding phosphorothioates (PS) into the sequence.
Publisher: MDPI AG
Date: 19-06-2020
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.
Publisher: Informa UK Limited
Date: 30-01-2022
DOI: 10.1080/15257770.2022.2029883
Abstract: Novel 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues (
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 .
Publisher: Wiley
Date: 15-03-2017
Publisher: MDPI AG
Date: 31-03-2020
DOI: 10.3390/IJMS21072434
Abstract: Alpha-l-Locked nucleic acid (α-l-LNA) is a stereoisomeric analogue of locked nucleic acid (LNA), which possesses excellent biophysical properties and also exhibits high target binding affinity to complementary oligonucleotide sequences and resistance to nuclease degradations. Therefore, α-l-LNA nucleotides could be utilised to develop stable antisense oligonucleotides (AO), which can be truncated without compromising the integrity and efficacy of the AO. In this study, we explored the potential of α-l-LNA nucleotides-modified antisense oligonucleotides to modulate splicing by inducing Dmd exon-23 skipping in mdx mouse myoblasts in vitro. For this purpose, we have synthesised and systematically evaluated the efficacy of α-l-LNA-modified 2′-O-methyl phosphorothioate (2′-OMePS) AOs of three different sizes including 20mer, 18mer and 16mer AOs in parallel to fully-modified 2′-OMePS control AOs. Our results demonstrated that the 18mer and 16mer truncated AO variants showed slightly better exon-skipping efficacy when compared with the fully-23 modified 2′-OMePS control AOs, in addition to showing low cytotoxicity. As there was no previous report on using α-l-LNA-modified AOs in splice modulation, we firmly believe that this initial study could be beneficial to further explore and expand the scope of α-l-LNA-modified AO therapeutic molecules.
No related grants have been discovered for Rakesh Veedu.