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Precision Nucleic Acid Therapeutics
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Precision Nucleic Acid Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Role of Xenobiotics".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 19491

Special Issue Editor

Prof. Dr. Rakesh N. Veedu

E-Mail Website
Guest Editor
Centre for Molecular Medicine and Innovative Therapeutics, and Perron Institute for Neurological & Translational Science, Murdoch University, Perth, Australia
Interests: antisense oligonucleotides; siRNA; aptamers; miRNA; DNAzymes; triplex forming oligonucleotides; chemically-modified oligonucleotides; oligonucleotide delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oligonucleotide therapeutic approaches, including antisense oligonucleotides, siRNA, aptamers, microRNA mimics, antimiRs, and DNAzymes, continue to demonstrate great potential in developing drugs for the treatment of various inherited and acquired diseases. So far, eight antisense oligonucleotide drugs (Vitravene, Kynamro, Exondys 51, Spinraza, Tegsedi, Waylivra, Milasen, and Vyondys 53), two siRNA drugs (Onpattro and Givlaari), and one aptamer drug (Macugen) have received approvals for clinical use, and notably, eight of them were approved in the last five years alone. The use of chemically modified nucleic acids are paramount towards developing successful oligonucleotide drugs, but so far only a very small number of nucleic acid chemistries have been utilised in clinical developments. Although the oligonucleotide therapeutics field has progressed significantly in the last three decades, delivery efficacy, tissue-specific targeting, and the cost of therapy still remain as major challenges. This Special Issue is initiated to further promote the advancements of the field in all aspects of functional nucleic acid therapeutic developments, and provides an opportunity to share your quality research in a great journal.

Prof. Dr. Rakesh N. Veedu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antisense oligonucleotides
  • siRNA
  • Aptamers
  • miRNA mimics
  • AntimiRs
  • DNAzymes
  • Triplex-forming oligonucleotides
  • Oligonucleotide delivery
  • Chemically-modified oligonucleotides

Published Papers (5 papers)

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Research

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13 pages, 2998 KiB  
Article
Antisense Oligonucleotide Induction of the hnRNPA1b Isoform Affects Pre-mRNA Splicing of SMN2 in SMA Type I Fibroblasts
by Jarichad Toosaranont, Sukanya Ruschadaariyachat, Warasinee Mujchariyakul, Jantarika Kumar Arora, Varodom Charoensawan, Bhoom Suktitipat, Thomas N. Palmer, Sue Fletcher, Steve D. Wilton and Chalermchai Mitrpant
Int. J. Mol. Sci. 2022, 23(7), 3937; https://doi.org/10.3390/ijms23073937 - 01 Apr 2022
Viewed by 2669
Abstract
Spinal muscular atrophy (SMA) is a severe, debilitating neuromuscular condition characterised by loss of motor neurons and progressive muscle wasting. SMA is caused by a loss of expression of SMN1 that encodes the survival motor neuron (SMN) protein necessary for the survival of [...] Read more.
Spinal muscular atrophy (SMA) is a severe, debilitating neuromuscular condition characterised by loss of motor neurons and progressive muscle wasting. SMA is caused by a loss of expression of SMN1 that encodes the survival motor neuron (SMN) protein necessary for the survival of motor neurons. Restoration of SMN expression through increased inclusion of SMN2 exon 7 is known to ameliorate symptoms in SMA patients. As a consequence, regulation of pre-mRNA splicing of SMN2 could provide a potential molecular therapy for SMA. In this study, we explored if splice switching antisense oligonucleotides could redirect the splicing repressor hnRNPA1 to the hnRNPA1b isoform and restore SMN expression in fibroblasts from a type I SMA patient. Antisense oligonucleotides (AOs) were designed to promote exon 7b retention in the mature mRNA and induce the hnRNPA1b isoform. RT-PCR and western blot analysis were used to assess and monitor the efficiency of different AO combinations. A combination of AOs targeting multiple silencing motifs in hnRNPA1 pre-mRNA led to robust hnRNPA1b induction, which, in turn, significantly increased expression of full-length SMN (FL-SMN) protein. A combination of PMOs targeting the same motifs also strongly induced hnRNPA1b isoform, but surprisingly SMN2 exon 5 skipping was detected, and the PMO cocktail did not lead to a significant increase in expression of FL-SMN protein. We further performed RNA sequencing to assess the genome-wide effects of hnRNPA1b induction. Some 3244 genes were differentially expressed between the hnRNPA1b-induced and untreated SMA fibroblasts, which are functionally enriched in cell cycle and chromosome segregation processes. RT-PCR analysis demonstrated that expression of the master regulator of these enrichment pathways, MYBL2 and FOXM1B, were reduced in response to PMO treatment. These findings suggested that induction of hnRNPA1b can promote SMN protein expression, but not at sufficient levels to be clinically relevant. Full article
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
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16 pages, 3745 KiB  
Article
An Influence of Modification with Phosphoryl Guanidine Combined with a 2′-O-Methyl or 2′-Fluoro Group on the Small-Interfering-RNA Effect
by Anna S. Pavlova, Kristina I. Yakovleva, Anna V. Epanchitseva, Maxim S. Kupryushkin, Inna A. Pyshnaya, Dmitrii V. Pyshnyi, Elena I. Ryabchikova and Ilya S. Dovydenko
Int. J. Mol. Sci. 2021, 22(18), 9784; https://doi.org/10.3390/ijms22189784 - 10 Sep 2021
Cited by 6 | Viewed by 2475
Abstract
Small interfering RNA (siRNA) is the most important tool for the manipulation of mRNA expression and needs protection from intracellular nucleases when delivered into the cell. In this work, we examined the effects of siRNA modification with the phosphoryl guanidine (PG) group, which, [...] Read more.
Small interfering RNA (siRNA) is the most important tool for the manipulation of mRNA expression and needs protection from intracellular nucleases when delivered into the cell. In this work, we examined the effects of siRNA modification with the phosphoryl guanidine (PG) group, which, as shown earlier, makes oligodeoxynucleotides resistant to snake venom phosphodiesterase. We obtained a set of siRNAs containing combined modifications PG/2′-O-methyl (2′-OMe) or PG/2′-fluoro (2′-F); biophysical and biochemical properties were characterized for each duplex. We used the UV-melting approach to estimate the thermostability of the duplexes and RNAse A degradation assays to determine their stability. The ability to induce silencing was tested in cultured cells stably expressing green fluorescent protein. The introduction of the PG group as a rule decreased the thermodynamic stability of siRNA. At the same time, the siRNAs carrying PG groups showed increased resistance to RNase A. A gene silencing experiment indicated that the PG-modified siRNA retained its activity if the modifications were introduced into the passenger strand. Full article
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
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15 pages, 5671 KiB  
Article
Design and In Vitro Evaluation of Splice-Switching Oligonucleotides Bearing Locked Nucleic Acids, Amido-Bridged Nucleic Acids, and Guanidine-Bridged Nucleic Acids
by Takenori Shimo, Yusuke Nakatsuji, Keisuke Tachibana and Satoshi Obika
Int. J. Mol. Sci. 2021, 22(7), 3526; https://doi.org/10.3390/ijms22073526 - 29 Mar 2021
Cited by 2 | Viewed by 3156
Abstract
Our group previously developed a series of bridged nucleic acids (BNAs), including locked nucleic acids (LNAs), amido-bridged nucleic acids (AmNAs), and guanidine-bridged nucleic acids (GuNAs), to impart specific characteristics to oligonucleotides such as high-affinity binding and enhanced enzymatic resistance. In this study, we [...] Read more.
Our group previously developed a series of bridged nucleic acids (BNAs), including locked nucleic acids (LNAs), amido-bridged nucleic acids (AmNAs), and guanidine-bridged nucleic acids (GuNAs), to impart specific characteristics to oligonucleotides such as high-affinity binding and enhanced enzymatic resistance. In this study, we designed a series of LNA-, AmNA-, and GuNA-modified splice-switching oligonucleotides (SSOs) with different lengths and content modifications. We measured the melting temperature (Tm) of each designed SSO to investigate its binding affinity for RNA strands. We also investigated whether the single-stranded SSOs formed secondary structures using UV melting analysis without complementary RNA. As a result, the AmNA-modified SSOs showed almost the same Tm values as the LNA-modified SSOs, with decreased secondary structure formation in the former. In contrast, the GuNA-modified SSOs showed slightly lower Tm values than the LNA-modified SSOs, with no inhibition of secondary structures. We also evaluated the exon skipping activities of the BNAs in vitro at both the mRNA and protein expression levels. We found that both AmNA-modified SSOs and GuNA-modified SSOs showed higher exon skipping activities than LNA-modified SSOs but each class must be appropriately designed in terms of length and modification content. Full article
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
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15 pages, 1766 KiB  
Article
Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1
by Kristin A. Ham, May Thandar Aung-Htut, Sue Fletcher and Steve D. Wilton
Int. J. Mol. Sci. 2020, 21(20), 7705; https://doi.org/10.3390/ijms21207705 - 18 Oct 2020
Cited by 11 | Viewed by 2682
Abstract
The COL7A1 gene encodes homotrimer fibrils essential for anchoring dermal and epidermal layers, and pathogenic mutations in COL7A1 can cause recessive or dominant dystrophic epidermolysis bullosa. As a monogenic disease gene, COL7A1 constitutes a potential target for antisense oligomer-mediated exon skipping, a therapy [...] Read more.
The COL7A1 gene encodes homotrimer fibrils essential for anchoring dermal and epidermal layers, and pathogenic mutations in COL7A1 can cause recessive or dominant dystrophic epidermolysis bullosa. As a monogenic disease gene, COL7A1 constitutes a potential target for antisense oligomer-mediated exon skipping, a therapy applicable to a growing number of other genetic disorders. However, certain characteristics of COL7A1: many exons, low average intron size, and repetitive and guanine-cytosine rich coding sequence, present challenges to the design of specific and effective antisense oligomers. While targeting COL7A1 exons 10 and 73 for excision from the mature mRNA, we discovered that antisense oligomers comprised of 2′-O-methyl modified bases on a phosphorothioate backbone and phosphorodiamidate morpholino oligomers produced similar, but distinctive, splicing patterns including excision of adjacent nontargeted exons and/or retention of nearby introns in some transcripts. We found that the nonsequential splicing of certain introns may alter pre-mRNA processing during antisense oligomer-mediated exon skipping and, therefore, additional studies are required to determine if the order of intron removal influences multiexon skipping and/or intron retention in processing of the COL7A1 pre-mRNA. Full article
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
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Review

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27 pages, 1840 KiB  
Review
Recent Advances in Oligonucleotide Therapeutics in Oncology
by Haoyu Xiong, Rakesh N. Veedu and Sarah D. Diermeier
Int. J. Mol. Sci. 2021, 22(7), 3295; https://doi.org/10.3390/ijms22073295 - 24 Mar 2021
Cited by 96 | Viewed by 7338
Abstract
Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting [...] Read more.
Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, and aptamers, show promising clinical outcomes for disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, and macular degeneration. While no approved oligonucleotide drug currently exists for any type of cancer, results obtained in preclinical studies and clinical trials are encouraging. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in oncology, review current clinical trials, and discuss associated challenges. Full article
(This article belongs to the Special Issue Precision Nucleic Acid Therapeutics)
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