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Transcriptional Therapy and Nucleic Acid-Based Therapeutics: From Molecular Targets to Preclinical Studies 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 May 2024 | Viewed by 3860

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Special Issue Editor

Dr. Vincenza Barresi

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Guest Editor

Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
Interests: genomics; transcriptomics; cancer; molecular biomarkers; cancer driver genes; proteases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last few decades, the exponential growth of genomic information has become crucial to develop new treatments based on molecular tools able to transcriptionally or post-transcriptionally modify the expression of coding and non-coding RNA. To date, antisense oligonucleotides (ASOs), apatmers and RNA interference (RNAi), and CRISPR/Cas9 systems are the most common tools used for transcriptional therapy, and some of these tools have been approved by regulatory authorities for the therapy of diseases such as age-related macular degeneration (AMD), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA). These approaches are exciting and advantageous for both monogenic and polygenic diseases. In the latter case, autoimmune and inflammatory diseases, neurological diseases, cancer, metabolic syndrome, and obesity represent the areas in which transcriptional therapy and nucleic acid-based therapeutics are continuing to expand.

This Special Issue will gather papers reporting on investigations focused on concepts, interpretations, and experiments concerning nucleic acid-based therapeutics, ranging from the identification of molecular targets to their application in preclinical studies.

Dr. Vincenza Barresi
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 oligonucleotide (ASO)
RNA interference (RNAi)
CRISPR/Cas9
miRNA
nucleic acid-based therapeutics
long non-coding RNA
splicing modification
transcript-targeted therapy
cancer therapy
genetic diseases

Published Papers (3 papers)

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Research

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15 pages, 2017 KiB

Open AccessArticle

The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Gene Expression in a Cell-Free Transcription/Translation System

by Agnieszka Polak, Grzegorz Machnik, Łukasz Bułdak, Jarosław Ruczyński, Katarzyna Prochera, Oliwia Bujak, Piotr Mucha, Piotr Rekowski and Bogusław Okopień

Int. J. Mol. Sci. 2024, 25(3), 1463; https://doi.org/10.3390/ijms25031463 - 25 Jan 2024

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Abstract

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran—a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate–sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT–real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection. Full article

(This article belongs to the Special Issue Transcriptional Therapy and Nucleic Acid-Based Therapeutics: From Molecular Targets to Preclinical Studies 2.0)

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15 pages, 4483 KiB

Open AccessArticle

Chondrocyte Thrombomodulin Protects against Osteoarthritis

by Lin Kang, Ai-Lun Yang, Chao-Han Lai, Tsan-Ju Chen, Sung-Yen Lin, Yan-Hsiung Wang, Chau-Zen Wang, Edward M. Conway, Hua-Lin Wu, Mei-Ling Ho, Je-Ken Chang, Chung-Hwan Chen and Tsung-Lin Cheng

Int. J. Mol. Sci. 2023, 24(11), 9522; https://doi.org/10.3390/ijms24119522 - 30 May 2023

Viewed by 1564

Abstract

Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TM^LeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1β (IL-1β)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TM^LeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders. Full article

(This article belongs to the Special Issue Transcriptional Therapy and Nucleic Acid-Based Therapeutics: From Molecular Targets to Preclinical Studies 2.0)

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Review

Jump to: Research

18 pages, 1741 KiB

Open AccessReview

by José Luis García-Giménez, Wiam Saadi, Angel L. Ortega, Agustin Lahoz, Guillermo Suay, Julián Carretero, Javier Pereda, Ahlam Fatmi, Federico V. Pallardó and Salvador Mena-Molla

Int. J. Mol. Sci. 2024, 25(3), 1737; https://doi.org/10.3390/ijms25031737 - 01 Feb 2024

Viewed by 909

Abstract

The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs. As a result of this systematic review, we have stratified the miRNA landscape into (i) miRNAs whose levels directly modulate response to ICIs, (ii) miRNAs whose expression is modulated by ICIs, and (iii) miRNAs that directly elicit toxic effects or participate in immune-related adverse events (irAEs) caused by ICIs. Full article

(This article belongs to the Special Issue Transcriptional Therapy and Nucleic Acid-Based Therapeutics: From Molecular Targets to Preclinical Studies 2.0)

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