Challenges identifying efficacious miRNA therapeutics for cancer

AbstractCholangiocarcinomas (CCAs) are tumors with a dismal prognosis. Early diagnosis is a key challenge because of the lack of specific symptoms, and the curability rate is low due to the difficulty in achieving a radical resection and the intrinsic chemoresistance of CCA cells. Noncoding RNAs (ncRNAs) are transcripts that are not translated into proteins but exert their functional role by regulating the transcription and translation of other genes. The discovery of the first ncRNA dates back to 1993 when the microRNA (miRNA) lin-4 was discovered in Caenorhabditis elegans. Only 10 years later, miRNAs were shown to play an oncogenic role in cancer cells and within 20 years miRNA therapeutics were tested in humans. Here, the authors review the latest evidence for a role for ncRNAs in CCA and discuss the promise and challenges associated with the introduction of ncRNAs into clinical practice.

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Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer

Biophysical Reviews ◽

10.1007/s12551-017-0392-1 ◽

2018 ◽

Vol 10 (1) ◽

pp. 69-86 ◽

Cited By ~ 57

Author(s):

Tamkin Ahmadzada ◽

Glen Reid ◽

David R. McKenzie

Keyword(s):

Breast Cancer ◽

Delivery Systems ◽

Nanoparticle Delivery ◽

Mirna Therapeutics

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MicroRNA-based therapeutics in cardiovascular disease: screening and delivery to the target

Biochemical Society Transactions ◽

10.1042/bst20170037 ◽

2017 ◽

Vol 46 (1) ◽

pp. 11-21 ◽

Cited By ~ 35

Author(s):

David Mellis ◽

Andrea Caporali

Keyword(s):

Targeted Delivery ◽

Transcriptional Regulators ◽

Messenger Rnas ◽

Biological Responses ◽

Cardiovascular Biology ◽

Non Coding Rnas ◽

Novel Approaches ◽

Cardiovascular Cells ◽

Mirna Therapeutics ◽

Mirna Targeting

MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides, which have increasingly been recognized as potent post-transcriptional regulators of gene expression. MiRNA targeting is defined by the complementarities between positions 2–8 of miRNA 5′-end with generally the 3′-untranslated region of target mRNAs (messenger RNAs). The capacity of miRNAs to simultaneously inhibit many different mRNAs allows for an amplification of biological responses. Hence, miRNAs are extremely attractive targets for therapeutic regulation in several diseases, including cardiovascular. Novel approaches are emerging to identify the miRNA functions in cardiovascular biology processes and to improve miRNA delivery in the heart and vasculature. In the present study, we provide an overview of current studies of miRNA functions in cardiovascular cells by the use of high-content screening. We also discuss the challenge to achieve a safe and targeted delivery of miRNA therapeutics in cardiovascular cells.

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MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.773083 ◽

2021 ◽

Vol 8 ◽

Author(s):

Huatao Zhou ◽

Weijie Tang ◽

Jinfu Yang ◽

Jun Peng ◽

Jianjun Guo ◽

...

Keyword(s):

Heart Failure ◽

Heart Function ◽

The Body ◽

Chemical Modifications ◽

Non Coding Rna ◽

New Directions ◽

Future Challenges ◽

Flow Through ◽

Mirna Therapeutics ◽

Novel Therapeutic

Heart failure (HF) describes a group of manifestations caused by the failure of heart function as a pump that supports blood flow through the body. MicroRNAs (miRNAs), as one type of non-coding RNA molecule, have crucial roles in the etiology of HF. Accordingly, miRNAs related to HF may represent potential novel therapeutic targets. In this review, we first discuss the different roles of miRNAs in the development and diseases of the heart. We then outline commonly used miRNA chemical modifications and delivery systems. Further, we summarize the opportunities and challenges for HF-related miRNA therapeutics targets, and discuss the first clinical trial of an antisense drug (CDR132L) in patients with HF. Finally, we outline current and future challenges and potential new directions for miRNA-based therapeutics for HF.

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microRNAs in Cardiovascular Disease: Small Molecules but Big Roles

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190808160241 ◽

2019 ◽

Vol 19 (21) ◽

pp. 1918-1947 ◽

Cited By ~ 8

Author(s):

Bingqian Yan ◽

Huijing Wang ◽

Yao Tan ◽

Wei Fu

Keyword(s):

Cardiovascular Diseases ◽

Therapeutic Potential ◽

Biological Effects ◽

Aberrant Expression ◽

Therapeutic Trials ◽

Cellular Phenotypes ◽

And Control ◽

Mirna Therapeutics

microRNAs (miRNAs) are an evolutionarily conserved class of small single-stranded noncoding RNAs. The aberrant expression of specific miRNAs has been implicated in the development and progression of diverse cardiovascular diseases. For many decades, miRNA therapeutics has flourished, taking advantage of the fact that miRNAs can modulate gene expression and control cellular phenotypes at the posttranscriptional level. Genetic replacement or knockdown of target miRNAs by chemical molecules, referred to as miRNA mimics or inhibitors, has been used to reverse their abnormal expression as well as their adverse biological effects in vitro and in vivo in an effort to fully implement the therapeutic potential of miRNA-targeting treatment. However, the limitations of the chemical structure and delivery systems are hindering progress towards clinical translation. Here, we focus on the regulatory mechanisms and therapeutic trials of several representative miRNAs in the context of specific cardiovascular diseases; from this basic perspective, we evaluate chemical modifications and delivery vectors of miRNA-based chemical molecules and consider the underlying challenges of miRNA therapeutics as well as the clinical perspectives on their applications.

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HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms19113295 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3295 ◽

Cited By ~ 11

Author(s):

Hongli Zhang ◽

Qingqing Feng ◽

Wei-Dong Chen ◽

Yan-Dong Wang

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Digestive System ◽

Therapeutic Potential ◽

Signaling Networks ◽

Preclinical Studies ◽

Current Review ◽

Promising Therapeutic Target ◽

Signaling Inhibitors ◽

Mirna Therapeutics

The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

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MiRNA therapeutics based on logic circuits of biological pathways

BMC Bioinformatics ◽

10.1186/s12859-019-2881-7 ◽

2019 ◽

Vol 20 (S9) ◽

Cited By ~ 4

Author(s):

Valeria Boscaino ◽

Antonino Fiannaca ◽

Laura La Paglia ◽

Massimo La Rosa ◽

Riccardo Rizzo ◽

...

Keyword(s):

Cancer Therapy ◽

Circuit Simulation ◽

Logic Gates ◽

Digital Circuit ◽

Signalling Pathway ◽

Signalling Pathways ◽

Therapy Design ◽

Mirna Therapeutics

Abstract Background In silico experiments, with the aid of computer simulation, speed up the process of in vitro or in vivo experiments. Cancer therapy design is often based on signalling pathway. MicroRNAs (miRNA) are small non-coding RNA molecules. In several kinds of diseases, including cancer, hepatitis and cardiovascular diseases, they are often deregulated, acting as oncogenes or tumor suppressors. miRNA therapeutics is based on two main kinds of molecules injection: miRNA mimics, which consists of injection of molecules that mimic the targeted miRNA, and antagomiR, which consists of injection of molecules inhibiting the targeted miRNA. Nowadays, the research is focused on miRNA therapeutics. This paper addresses cancer related signalling pathways to investigate miRNA therapeutics. Results In order to prove our approach, we present two different case studies: non-small cell lung cancer and melanoma. KEGG signalling pathways are modelled by a digital circuit. A logic value of 1 is linked to the expression of the corresponding gene. A logic value of 0 is linked to the absence (not expressed) gene. All possible relationships provided by a signalling pathway are modelled by logic gates. Mutations, derived according to the literature, are introduced and modelled as well. The modelling approach and analysis are widely discussed within the paper. MiRNA therapeutics is investigated by the digital circuit analysis. The most effective miRNA and combination of miRNAs, in terms of reduction of pathogenic conditions, are obtained. A discussion of obtained results in comparison with literature data is provided. Results are confirmed by existing data. Conclusions The proposed study is based on drug discovery and miRNA therapeutics and uses a digital circuit simulation of a cancer pathway. Using this simulation, the most effective combination of drugs and miRNAs for mutated cancer therapy design are obtained and these results were validated by the literature. The proposed modelling and analysis approach can be applied to each human disease, starting from the corresponding signalling pathway.

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