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RNA Therapeutics and Disease: A New Frontier in Medicine

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

Deadline for manuscript submissions: closed (10 February 2024) | Viewed by 13831

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Special Issue Editors

Dr. Annalisa Di Ruscio

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Guest Editor

Harvard Medical School, Beth Israel Deaconess Medical Centre, Boston, MA, USA

Dr. Carla Lucia Esposito

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Guest Editor

Istituto per l’Endocrinologia e l’Oncologia Sperimentale del CNR ‘‘G. Salvatore’’, Via S. Pansini 5, 80131 Naples, Italy
Interests: aptamers; cancer; targeted delivery; SELEX
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The boost of high-throughput technologies in the last decade has revealed a plethora of unexpected RNAs with no obvious coding capacities, termed noncoding RNAs (ncRNAs). This noncoding transcription, for a long time deemed to be nothing more than “transcriptional noise”, has been demonstrated to play critical roles across multiple biological pathways through a variety of different mechanisms—for instance, by regulating chromatin modifications, or by affecting mRNA stability and translation. Long and short ncRNAs regulate gene expression at almost every step. The revolution in RNA biology and the introduction of novel RNA-based gene editing approaches (i.e., CRISPR) have ushered in the new era of RNA therapeutics. These molecules mimic or antagonize the function of natural existing ncRNAs.

By tapping into RNA biology, RNA-based drugs are emerging as an innovative, precise, and broad approach for the treatment of pathological conditions such as hepatic viruses, liver-centric genetic diseases, cancer, cardiometabolic or neurological disorders, and, more recently, as a novel platform for vaccine development. Hence, RNA-based drugs hold promise to expand the domain of “druggable” targets beyond that of conventional small molecules and biologics.

This Special Issue aims at elucidating the latest advances in RNA Therapeutics (including small interfering RNAs (siRNAs), microRNAs (miRs)/antimiRs, mRNA, antisense oligonucleotides (ASO), aptamers, and CRISPR-based approaches) in diseases. We welcome the submission of both original research and review articles discussing the state-of-the-art of RNA-based drugs with potential clinical benefits in areas related to cancer, immunotherapy, neurology, metabolic disorders, and infectious diseases.

Dr. Annalisa Di Ruscio
Dr. Carla Lucia Esposito
Guest Editors

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

RNA therapeutics
RNA biology
Cancer
Immunotherapy
Acquired and inherited neurological conditions
Metabolic disorders
Infectious disease
Vaccine
COVID-19

Published Papers (4 papers)

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Research

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13 pages, 1025 KiB

Open AccessArticle

Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification

by Ivan V. Chernikov, Ul’yana A. Ponomareva, Mariya I. Meschaninova, Irina K. Bachkova, Valentin V. Vlassov, Marina A. Zenkova and Elena L. Chernolovskaya

Molecules 2024, 29(4), 786; https://doi.org/10.3390/molecules29040786 - 08 Feb 2024

Viewed by 910

Abstract

Cholesterol siRNA conjugates attract attention because they allow the delivery of siRNA into cells without the use of transfection agents. In this study, we compared the efficacy and duration of silencing induced by cholesterol conjugates of selectively and totally modified siRNAs and their heteroduplexes of the same sequence and explored the impact of linker length between the 3′ end of the sense strand of siRNA and cholesterol on the silencing activity of “light” and “heavy” modified siRNAs. All 3′-cholesterol conjugates were equally active under transfection, but the conjugate with a C3 linker was less active than those with longer linkers (C8 and C15) in a carrier-free mode. At the same time, they were significantly inferior in activity to the 5′-cholesterol conjugate. Shortening the sense strand carrying cholesterol by two nucleotides from the 3′-end did not have a significant effect on the activity of the conjugate. Replacing the antisense strand or both strands with fully modified ones had a significant effect on silencing as well as improving the duration in transfection-mediated and carrier-free modes. A significant 78% suppression of MDR1 gene expression in KB-8-5 xenograft tumors developed in mice promises an advantage from the use of fully modified siRNA cholesterol conjugates in combination chemotherapy. Full article

(This article belongs to the Special Issue RNA Therapeutics and Disease: A New Frontier in Medicine)

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Review

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26 pages, 1527 KiB

Open AccessReview

Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development

by Anais M. Quemener, Maria Laura Centomo, Scott L. Sax and Riccardo Panella

Molecules 2022, 27(2), 536; https://doi.org/10.3390/molecules27020536 - 15 Jan 2022

Cited by 39 | Viewed by 5640

Abstract

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences of nucleotides are designed to precisely target other oligonucleotides, usually RNA species, and are modified to protect them from degradation by nucleases. Their specificity is due to their sequence, so it is possible to target any RNA sequence that is already known. These molecules are very versatile and adaptable given that their sequence and chemistry can be custom manufactured. Based on the chemistry being used, their activity may significantly change and their effects on cell function and phenotypes can differ dramatically. While some will cause the target RNA to decay, others will only bind to the target and act as a steric blocker. Their incredible versatility is the key to manipulating several aspects of nucleic acid function as well as their process, and alter the transcriptome profile of a specific cell type or tissue. For example, they can be used to modify splicing or mask specific sites on a target. The entire design rather than just the sequence is essential to ensuring the specificity of the ASO to its target. Thus, it is vitally important to ensure that the complete process of drug design and testing is taken into account. ASOs’ adaptability is a considerable advantage, and over the past decades has allowed multiple new drugs to be approved. This, in turn, has had a significant and positive impact on patient lives. Given current challenges presented by the COVID-19 pandemic, it is necessary to find new therapeutic strategies that would complement the vaccination efforts being used across the globe. ASOs may be a very powerful tool that can be used to target the virus RNA and provide a therapeutic paradigm. The proof of the efficacy of ASOs as an anti-viral agent is long-standing, yet no molecule currently has FDA approval. The emergence and widespread use of RNA vaccines during this health crisis might provide an ideal opportunity to develop the first anti-viral ASOs on the market. In this review, we describe the story of ASOs, the different characteristics of their chemistry, and how their characteristics translate into research and as a clinical tool. Full article

(This article belongs to the Special Issue RNA Therapeutics and Disease: A New Frontier in Medicine)

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10 pages, 1003 KiB

Open AccessReview

RNA Activation—A Novel Approach to Therapeutically Upregulate Gene Transcription

by Choon Ping Tan, Laura Sinigaglia, Valentí Gomez, Joanna Nicholls and Nagy A. Habib

Molecules 2021, 26(21), 6530; https://doi.org/10.3390/molecules26216530 - 28 Oct 2021

Cited by 14 | Viewed by 4173

Abstract

RNA activation (RNAa) is a mechanism whereby RNA oligos complementary to genomic sequences around the promoter region of genes increase the transcription output of their target gene. Small activating RNA (saRNA) mediate RNAa through interaction with protein co-factors to facilitate RNA polymerase II activity and nucleosome remodeling. As saRNA are small, versatile and safe, they represent a new class of therapeutics that can rescue the downregulation of critical genes in disease settings. This review highlights our current understanding of saRNA biology and describes various examples of how saRNA are successfully used to treat various oncological, neurological and monogenic diseases. MTL-CEBPA, a first-in-class compound that reverses CEBPA downregulation in oncogenic processes using CEBPA-51 saRNA has entered clinical trial for the treatment of hepatocellular carcinoma (HCC). Preclinical models demonstrate that MTL-CEBPA reverses the immunosuppressive effects of myeloid cells and allows for the synergistic enhancement of other anticancer drugs. Encouraging results led to the initiation of a clinical trial combining MTL-CEBPA with a PD-1 inhibitor for treatment of solid tumors. Full article

(This article belongs to the Special Issue RNA Therapeutics and Disease: A New Frontier in Medicine)

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7 pages, 676 KiB

Open AccessReview

Role of Regulatory Non-Coding RNAs in Aggressive Thyroid Cancer: Prospective Applications of Neural Network Analysis

by Asumi Iesato and Carmelo Nucera

Molecules 2021, 26(10), 3022; https://doi.org/10.3390/molecules26103022 - 19 May 2021

Cited by 5 | Viewed by 2197

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy. Most TCs have a favorable prognosis, whereas anaplastic thyroid carcinoma (ATC) is a lethal form of cancer. Different genetic and epigenetic alterations have been identified in aggressive forms of TC such as ATC. Non-coding RNAs (ncRNAs) represent functional regulatory molecules that control chromatin reprogramming, including transcriptional and post-transcriptional mechanisms. Intriguingly, they also play an important role as coordinators of complex gene regulatory networks (GRNs) in cancer. GRN analysis can model molecular regulation in different species. Neural networks are robust computing systems for learning and modeling the dynamics or dependencies between genes, and are used for the reconstruction of large data sets. Canonical network motifs are coordinated by ncRNAs through gene production from each transcript as well as through the generation of a single transcript that gives rise to multiple functional products by post-transcriptional modifications. In non-canonical network motifs, ncRNAs interact through binding to proteins and/or protein complexes and regulate their functions. This article overviews the potential role of ncRNAs GRNs in TC. It also suggests prospective applications of deep neural network analysis to predict ncRNA molecular language for early detection and to determine the prognosis of TC. Validation of these analyses may help in the design of more effective and precise targeted therapies against aggressive TC. Full article

(This article belongs to the Special Issue RNA Therapeutics and Disease: A New Frontier in Medicine)

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