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Special Issue "siRNA Therapeutics: From Bench Lab to Clinics"

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 15584

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Dr. Cristina Romero-López

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Guest Editor

Department of Molecular Biology, Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), PTS Granada, Av. Conocimiento, Armilla, 18016 Granada, Spain
Interests: structural biology; aptamers; viral RNA genomes; functional RNA
Special Issues, Collections and Topics in MDPI journals

Dr. Alfredo Berzal-Herranz

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Guest Editor

Department of Molecular Biology, Instituto de Parasitología y Biomedicina López-Neyra, (IPBLN-CSIC), PTS Granada, Av del Conocimiento 17, 18016 Granada, Spain
Interests: antiviral nucleic acids; therapeutic RNA; aptamers; RNA inhibitors; structure/function of RNA; RNA viruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

It is our pleasure to invite you to contribute with original research or review manuscripts to a new Special Issue of the Pharmaceuticals journal, entitled “siRNA therapeutics: From Bench Lab to Clinics”.

The potential of siRNAs as molecular and therapeutic tools was already envisioned soon after their discovery in 1998. Since then, siRNA therapeutics have paved their pathway into clinics. This has been achieved by significant advances in targeted delivery and efficient siRNA stabilization in plasma and serum, concomitantly with the development of novel and powerful experimental tools employed in basic and applied research. Hence, the use of siRNAs in clinics can be considered the result of a close relationship between basic and applied science.

This Special Issue intends to collect both review and original research articles presenting the current state-of-the-art of siRNAs in clinics, either as diagnostic or therapeutic agents. Reports on the development of new carriers for nucleic acid tools and presentation of barriers and challenges that still need to be overcome for their effective use are also welcome.

Dr. Cristina Romero-López
Dr. Alfredo Berzal-Herranz
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. Pharmaceuticals 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 2900 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.

Published Papers (7 papers)

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Research

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Open AccessArticle

Tumor Suppressive Role of miR-342-5p and miR-491-5p in Human Osteosarcoma Cells

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Pharmaceuticals 2022, 15(3), 362; https://doi.org/10.3390/ph15030362 - 16 Mar 2022

Cited by 4 | Viewed by 1851

Abstract

Osteosarcomas are the most common type of malignant bone tumor. These tumors are characterized by the synthesis of an osteoid matrix. Current treatments are based on surgery and combination chemotherapy. However, for metastatic or recurrent tumors, chemotherapy is generally ineffective, and osteosarcomas are sometimes unresectable. Thus, the use of microRNAs (miRNAs) may represent an attractive alternative for the development of new therapies. Using high-throughput functional screening based on impedancemetry, we previously selected five miRNAs with potential chemosensitizing or antiproliferative effects on chondrosarcoma cells. We validated the tumor-suppressive activity of miR-491-5p and miR-342-5p in three chondrosarcoma cell lines. Here, we carried out individual functional validation of these five miRNAs in three osteosarcoma cell lines used as controls to evaluate their specificity of action on another type of bone sarcoma. The cytotoxic effects of miR-491-5p and miR-342-5p were also confirmed in osteosarcoma cells. Both miRNAs induced apoptosis. They increased Bcl-2 homologous antagonist killer (Bak) protein expression and directly targeted Bcl-2 lymphoma-extra large (Bcl-xL). MiR-342-5p also decreased B-cell lymphoma-2 (Bcl-2) protein expression, and miR-491-5p decreased that of Epidermal Growth Factor Receptor (EGFR). MiR-342-5p and miR-491-5p show tumor-suppressive activity in osteosarcomas. This study also confirms the potential of Bcl-xL as a therapeutic target in osteosarcomas. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Open AccessArticle

Peptide Nanoparticle-Mediated Combinatorial Delivery of Cancer-Related siRNAs for Synergistic Anti-Proliferative Activity in Triple Negative Breast Cancer Cells

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Pharmaceuticals 2021, 14(10), 957; https://doi.org/10.3390/ph14100957 - 23 Sep 2021

Cited by 3 | Viewed by 1608

Abstract

Triple negative breast cancer (TNBC) is one of the deadliest types of cancer for women of different age groups. Frequently this cancer does not respond to conservative treatment. Combinatorial RNAi can be suggested as an advanced approach to TNBC therapy. Due to the fact that TNBC cells overexpress chemokine receptor 4 we used modular L1 peptide-based nanoparticles modified with CXCR4 ligand for combinatorial delivery of siRNAs suppressing major transduction pathways. TNBC cell line MDA-MB-231 was used as a cellular model. Genes encoding the AQP3, CDC20, and COL4A2 proteins responsible for proliferative activity in TNBC cells were selected as RNAi targets. The siRNA binding ability of the carrier was studied at different charge ratios. The silencing specificity was demonstrated for all siRNAs studied. Alamar Blue proliferation assay has shown significant reduction in the anti-proliferative activity after combinatorial siRNA transfection compared to single siRNA delivery. The most significant synergistic effect has been demonstrated for combinatorial transfection of anti-COL4A2 and anti-CDC20 siRNAs what resulted in 1.5–2 fold inhibition of proliferation and migration of TNBC cells. Based on our findings, we have concluded that combinatorial treatment by CXCR4-ligand modified L1-polyplexes formed with AQP3, CDC20, and COL4A2 siRNAs effectively inhibits proliferation of TNBC cells and can be suggested as useful tool for RNAi-mediated cancer therapy. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Open AccessArticle

miR-16-5p Promotes Erythroid Maturation of Erythroleukemia Cells by Regulating Ribosome Biogenesis

Christos I. Papagiannopoulos

Nikoleta F. Theodoroula

and

Ioannis S. Vizirianakis

Pharmaceuticals 2021, 14(2), 137; https://doi.org/10.3390/ph14020137 - 09 Feb 2021

Cited by 4 | Viewed by 2077

Abstract

miRNAs constitute a class of non-coding RNA that act as powerful epigenetic regulators in animal and plant cells. In order to identify putative tumor-suppressor miRNAs we profiled the expression of various miRNAs during differentiation of erythroleukemia cells. RNA was purified before and after differentiation induction and subjected to quantitative RT-PCR. The majority of the miRNAs tested were found upregulated in differentiated cells with miR-16-5p showing the most significant increase. Functional studies using gain- and loss-of-function constructs proposed that miR-16-5p has a role in promoting the erythroid differentiation program of murine erythroleukemia (MEL) cells. In order to identify the underlying mechanism of action, we utilized bioinformatic in-silico platforms that incorporate predictions for the genes targeted by miR-16-5p. Interestingly, ribosome constituents, as well as ribosome biogenesis factors, were overrepresented among the miR-16-5p predicted gene targets. Accordingly, biochemical experiments showed that, indeed, miR-16-5p could modulate the levels of independent ribosomal proteins, and the overall ribosomal levels in cultured cells. In conclusion, miR-16-5p is identified as a differentiation-promoting agent in erythroleukemia cells, demonstrating antiproliferative activity, likely as a result of its ability to target the ribosomal machinery and restore any imbalanced activity imposed by the malignancy and the blockade of differentiation. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Review

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Open AccessReview

Potential Application of Small Interfering RNA in Gastro-Intestinal Tumors

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Pharmaceuticals 2022, 15(10), 1295; https://doi.org/10.3390/ph15101295 - 20 Oct 2022

Cited by 2 | Viewed by 1671

Abstract

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the mRNA of pathological genes, have the potential to be of therapeutic value. To be effective in the human body, siRNAs need to be protected against degradation. Additionally, they need to target the tumor, leaving the normal tissue untouched in an effort to preserve organ function. To accomplish these tasks, siRNAs have been formulated with smart delivery systems such has polymers and lipids. While siRNA protection is not particularly difficult to achieve, their targeting of tumor cells remains problematic. Here, after introducing the general features of gastrointestinal cancers, we describe siRNA characteristics together with representative delivery systems developed for gastrointestinal cancers. Afterward, we present a selection of research papers employing siRNAs against upper- and lower- gastrointestinal cancers. For the liver, we also consider papers using siRNAs to combat liver cirrhosis, a relevant risk factor for liver cancer development. Finally, we present a brief description of clinical trials employing siRNAs for gastrointestinal cancers. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Open AccessReview

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery

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Pharmaceuticals 2022, 15(10), 1276; https://doi.org/10.3390/ph15101276 - 17 Oct 2022

Cited by 3 | Viewed by 1641

Abstract

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising strategies to promote lung repair, due to incredible regenerative potential and typical immunomodulatory function, respectively. Extracellular vesicles (EVs), including exosomes and microvesicles, are cell-derived lipid-bilayer membrane vesicles that are secreted from virtually every cell and are involved in intercellular communication by delivering expansive biological cargos to recipients. This review provides a deep insight into the recent research progress concerning the effects of MSC and macrophage-associated EVs on the pathogenesis of pulmonary fibrosis. In addition to discussing their respective vital roles, we summarize the importance of cross-talk, as macrophages are vital for MSCs to exert their protective effects through two major patterns, including attenuating macrophage activation and M1 phenotype macrophage polarization. Moreover, miRNAs are selectively enriched into EVs as essential components, and consideration is given to the particular effects of EV-associated miRNAs. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Open AccessEditor’s ChoiceReview

Biotechnological Evolution of siRNA Molecules: From Bench Tool to the Refined Drug

Danielle de Brito e Cunha

Ana Beatriz Teixeira Frederico

Tamiris Azamor

Juliana Gil Melgaço

Patricia Cristina da Costa Neves

Ana Paula Dinis Ano Bom

Tatiana Martins Tilli

and

Sotiris Missailidis

Pharmaceuticals 2022, 15(5), 575; https://doi.org/10.3390/ph15050575 - 05 May 2022

Cited by 10 | Viewed by 4117

Abstract

The depth and versatility of siRNA technologies enable their use in disease targets that are undruggable by small molecules or that seek to achieve a refined turn-off of the genes for any therapeutic area. Major extracellular barriers are enzymatic degradation of siRNAs by serum endonucleases and RNAases, renal clearance of the siRNA delivery system, the impermeability of biological membranes for siRNA, activation of the immune system, plasma protein sequestration, and capillary endothelium crossing. To overcome the intrinsic difficulties of the use of siRNA molecules, therapeutic applications require nanometric delivery carriers aiming to protect double-strands and deliver molecules to target cells. This review discusses the history of siRNAs, siRNA design, and delivery strategies, with a focus on progress made regarding siRNA molecules in clinical trials and how siRNA has become a valuable asset for biopharmaceutical companies. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Open AccessReview

In Vitro Methods to Decipher the Structure of Viral RNA Genomes

Cristina Romero-López

Sara Esther Ramos-Lorente

and

Alfredo Berzal-Herranz

Pharmaceuticals 2021, 14(11), 1192; https://doi.org/10.3390/ph14111192 - 20 Nov 2021

Viewed by 1518

Abstract

RNA viruses encode essential information in their genomes as conserved structural elements that are involved in efficient viral protein synthesis, replication, and encapsidation. These elements can also establish complex networks of RNA-RNA interactions, the so-called RNA interactome, to shape the viral genome and control different events during intracellular infection. In recent years, targeting these conserved structural elements has become a promising strategy for the development of new antiviral tools due to their sequence and structural conservation. In this context, RNA-based specific therapeutic strategies, such as the use of siRNAs have been extensively pursued to target the genome of different viruses. Importantly, siRNA-mediated targeting is not a straightforward approach and its efficiency is highly dependent on the structure of the target region. Therefore, the knowledge of the viral structure is critical for the identification of potentially good target sites. Here, we describe detailed protocols used in our laboratory for the in vitro study of the structure of viral RNA genomes. These protocols include DMS (dimethylsulfate) probing, SHAPE (selective 2′-hydroxyl acylation analyzed by primer extension) analysis, and HMX (2′-hydroxyl molecular interference). These methodologies involve the use of high-throughput analysis techniques that provide extensive information about the 3D folding of the RNA under study and the structural tuning derived from the interactome activity. They are therefore a good tool for the development of new RNA-based antiviral compounds. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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Special Issue "siRNA Therapeutics: From Bench Lab to Clinics"

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