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Special Issue "Therapeutic Nucleic Acids: Past, Present, and Future"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Nanochemistry".

Deadline for manuscript submissions: closed (15 November 2018)

Special Issue Editor

Guest Editor
Dr. Marina A. Dobrovolskaia

Nanotechnology Characterization Lab, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Website | E-Mail
Interests: immunology; toxicology; nanoparticles

Special Issue Information

Dear Colleagues,

The goal of this Special Issue is to review achievements and lessons learned from basic research and translational studies related to moving therapeutic nucleic acids from bench to bedside. The issue will include review and research articles, focusing on both traditional nucleic acids (e.g., antisense oligonucleotides, siRNA) and a new generation molecules (e.g., sgRNA, DNA origami, DNA/RNA nanoparticles). Challenges with the delivery of therapeutic nucleic acids and solutions for overcoming the challenges will be addressed by experts in the field. Nanotechnology-based delivery platforms, safety, efficacy, biomarkers,  and appropriate in vivo/in vitro models will be considered. We welcome you to share your research findings, literature reviews and technical recommendations in the subject area by submitting your work to this Special Issue.

Dr. Marina A. Dobrovolskaia
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 papers will be 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. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • Therapeutic oligonucleotides
  • Therapeutic RNA (RNAi, miRNA, mRNA)
  • DNA origami
  • RNA nanoparticles
  • DNA nanoparticles

Published Papers (4 papers)

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Research

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Open AccessArticle RNA–Protein Interactions Prevent Long RNA Duplex Formation: Implications for the Design of RNA-Based Therapeutics
Molecules 2018, 23(12), 3329; https://doi.org/10.3390/molecules23123329 (registering DOI)
Received: 19 November 2018 / Revised: 12 December 2018 / Accepted: 13 December 2018 / Published: 15 December 2018
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Abstract
Cells frequently simultaneously express RNAs and cognate antisense transcripts without necessarily leading to the formation of RNA duplexes. Here, we present a novel transcriptome-wide experimental approach to ascertain the presence of accessible double-stranded RNA structures based on sequencing of RNA fragments longer than
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Cells frequently simultaneously express RNAs and cognate antisense transcripts without necessarily leading to the formation of RNA duplexes. Here, we present a novel transcriptome-wide experimental approach to ascertain the presence of accessible double-stranded RNA structures based on sequencing of RNA fragments longer than 18 nucleotides that were not degraded by single-strand cutting nucleases. We applied this approach to four different cell lines with respect to three different treatments (native cell lysate, removal of proteins, and removal of ribosomal RNA and proteins). We found that long accessible RNA duplexes were largely absent in native cell lysates, while the number of RNA duplexes was dramatically higher when proteins were removed. The majority of RNA duplexes involved ribosomal transcripts. The duplex formation between different non-ribosomal transcripts appears to be largely of a stochastic nature. These results suggest that cells are—via RNA-binding proteins—mostly devoid of long RNA duplexes, leading to low “noise” in the molecular patterns that are utilized by the innate immune system. These findings have implications for the design of RNA interference (RNAi)-based therapeutics by imposing structural constraints on designed RNA complexes that are intended to have specific properties with respect to Dicer cleavage and target gene downregulation. Full article
(This article belongs to the Special Issue Therapeutic Nucleic Acids: Past, Present, and Future)
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Open AccessCommunication Broccoli Fluorets: Split Aptamers as a User-Friendly Fluorescent Toolkit for Dynamic RNA Nanotechnology
Molecules 2018, 23(12), 3178; https://doi.org/10.3390/molecules23123178
Received: 7 November 2018 / Revised: 29 November 2018 / Accepted: 29 November 2018 / Published: 2 December 2018
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Abstract
RNA aptamers selected to bind fluorophores and activate their fluorescence offer a simple and modular way to visualize native RNAs in cells. Split aptamers which are inactive until the halves are brought within close proximity can become useful for visualizing the dynamic actions
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RNA aptamers selected to bind fluorophores and activate their fluorescence offer a simple and modular way to visualize native RNAs in cells. Split aptamers which are inactive until the halves are brought within close proximity can become useful for visualizing the dynamic actions of RNA assemblies and their interactions in real time with low background noise and eliminated necessity for covalently attached dyes. Here, we design and test several sets of F30 Broccoli aptamer splits, that we call fluorets, to compare their relative fluorescence and physicochemical stabilities. We show that the splits can be simply assembled either through one-pot thermal annealing or co-transcriptionally, thus allowing for direct tracking of transcription reactions via the fluorescent response. We suggest a set of rules that enable for the construction of responsive biomaterials that readily change their fluorescent behavior when various stimuli such as the presence of divalent ions, exposure to various nucleases, or changes in temperature are applied. We also show that the strand displacement approach can be used to program the controllable fluorescent responses in isothermal conditions. Overall, this work lays a foundation for the future development of dynamic systems for molecular computing which can be used to monitor real-time processes in cells and construct biocompatible logic gates. Full article
(This article belongs to the Special Issue Therapeutic Nucleic Acids: Past, Present, and Future)
Figures

Figure 1

Open AccessArticle Novel PEGylated Liposomes Enhance Immunostimulating Activity of isRNA
Molecules 2018, 23(12), 3101; https://doi.org/10.3390/molecules23123101
Received: 6 November 2018 / Revised: 23 November 2018 / Accepted: 24 November 2018 / Published: 27 November 2018
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Abstract
The performance of cationic liposomes for delivery of therapeutic nucleic acids in vivo can be improved and specifically tailored to certain types of cargo and target cells by incorporation of PEG-containing lipoconjugates in the cationic liposome’s composition. Here, we report on the synthesis
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The performance of cationic liposomes for delivery of therapeutic nucleic acids in vivo can be improved and specifically tailored to certain types of cargo and target cells by incorporation of PEG-containing lipoconjugates in the cationic liposome’s composition. Here, we report on the synthesis of novel PEG-containing lipoconjugates with molecular masses of PEG 800, 1500 and 2000 Da. PEG-containing lipoconjugates were used as one of the components in liposome preparation with the polycationic amphiphile 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetra-azahexacosan tetrahydrochloride (2X3) and the lipid-helper dioleoylphosphatidylethanolamine (DOPE). We demonstrate that increasing the length of the PEG chain reduces the transfection activity of liposomes in vitro, but improves the biodistribution, increases the circulation time in the bloodstream and enhances the interferon-inducing activity of immunostimulating RNA in vivo. Full article
(This article belongs to the Special Issue Therapeutic Nucleic Acids: Past, Present, and Future)
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Review

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Open AccessFeature PaperReview Self-Replicating RNA Viruses for RNA Therapeutics
Molecules 2018, 23(12), 3310; https://doi.org/10.3390/molecules23123310
Received: 16 November 2018 / Revised: 10 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
PDF Full-text (458 KB)
Abstract
Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene
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Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans. Full article
(This article belongs to the Special Issue Therapeutic Nucleic Acids: Past, Present, and Future)
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