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contents

July 2018, 12th

FEATURE STORY

● Non-coding RNAs in disease

BASIC SCIENCE

● Stability of circulating exosomal miRNAs in healthy subjects

PHYSIOPATHOLOGY

● Tissue and exosomal miRNA editing in non-small cell lung cancer
● Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis

THERAPEUTIC STRATEGIES

● Dynamic miRNA activity identifies therapeutic targets in trastuzumab-resistant HER2+ breast cancer

● Intestinal permeability, digestive stability and oral bioavailability of dietary small RNAs

● RNA therapeutics in cardiovascular disease

INDUSTRIAL LANDSCAPE & AGREEMENTS

● Regulus announces strategic update and corporate restructuring


July 2018, 12th

FEATURE STORY

Non-coding RNAs in disease

Non-coding RNAs (ncRNAs) are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly-growing number of studies has unravelled associations between aberrant non-coding RNA expression and human diseases. These associations have been extensively reviewed, often with the focus on a particular miRNA (family) or a selected disease/pathology. In this Mini-Review, we highlight a selection of studies in order to demonstrate the widescale involvement of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathophysiology of three types of diseases: cancer, cardiovascular and neurological disorders
The review appeared in July 4th online issue of FEBS Lett

Related Informations/Publications

- Viruses . 2018 Jul 3;10(7). miRNAs in Insects Infected by Animal and Plant Viruses. Monsanto-Hearne V & Johnson KN, The University of Queensland, Brisbane 4072, Australia
Link: Abstract
- Cell Mol Life Sci . 2018 Jun 30. Trans-spliced long non-coding RNA: an emerging regulator of pluripotency. Yu CY et al. Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
Link: Abstract

BASIC SCIENCE

Stability of circulating exosomal miRNAs in healthy subjects

Exosomes are nano-vesicles present in the circulation that are involved in cell-to-cell communication and regulation of different biological processes. MicroRNAs (miRNAs) are part of their cargo and are potential biomarkers. Methods of exosome isolation and the inter-individual and intra-individual variations in circulating miRNA exosomal cargo have been poorly investigated. A recent study aims for comparing two exosome isolation methods and to assess the stability of eleven plasma exosomal miRNAs over time. In addition to evaluate miRNA variability of both kits, the effect of freezing plasma before exosome isolation or freezing isolated exosomes on miRNA stability was also evaluated. MiRNA levels were tested in 7 healthy subjects who underwent four different blood extractions obtained in 4 consecutive weeks. One of the isolation kits displayed generally better amplification signals, and miRNAs from exosomes isolated after freezing the plasma had the highest levels. Intra-subject and inter-subject coefficients of variance were lower for the same isolation kit after freezing plasma.
The results appeared in July 09th online issue of Sci Rep

PHYSIOPATHOLOGY

Tissue and exosomal miRNA editing in non-small cell lung cancer

Tissue and exosomal miRNA editing in non-small cell lung cancer RNA editing in microRNAs has been recently proposed as a novel biomarker in cancer. American researchers have investigated RNA editing by leveraging small-RNA sequencing data from 87 NSCLC ( Non-Small Cell Lung Cancer ) samples paired with normal lung tissues from The Cancer Genome Atlas (TCGA) combined with 26 plasma-derived exosome samples from an independent cohort. Using both the editing levels and microRNA editing expression, they detected deregulated microRNA editing events between NSCLC tumor and normal tissues. Interestingly, and for the first time, they also detected editing sites in the microRNA cargo of circulating exosomes, providing the potential to non-invasively discriminate between normal and tumor samples. Of note, miR-411-5p edited in position 5 was significantly dysregulated in tissues as well as in exosomes of NSCLC patients, suggesting a potential targetome shift relevant to lung cancer biology.
The results appeared in July 05th online issue of Sci Rep

Related Informations / Publications

- BMB Rep . 2018 Jul 3. pii: 4198. Exosomes Derived from MicroRNA-584 Transfected Mesenchymal Stem Cells: Novel Alternative Therapeutic Vehicles for Cancer Therapy. Kim R et al. Pusan National University, Busan 46241, Korea
Results / Comments: The researchers propose a new targeted cancer therapy wherein exosomes derived from miRNA transfected MSCs could be used to modulate tumor progress as the anticancer vehicles
Link: Abstract
-Microrna. 2018 Jun 29. Functional role of microRNA-23b-3p in cancer biology. Grossi I et al. Division of Biology and Genetics, University of Brescia. Italy
Results / Comments: miR-23b-3p is generally considered a responsive molecular therapeutic target as reported in several in vitro and in vivo studies.
Link: Abstract

Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis

Exosomes, natural carriers of mRNAs, non-coding RNAs and proteins between donor and recipient cells, actively contribute to cell-cell communication. Italian researchers investigated the potential pro-fibrotic role of exosomes released by muscle-derived fibroblasts of Duchenne muscular dystrophy ( DMD ) patients, and of miRNAs carried by exosomes. By fibrosis focused array analysis they found that exosomes from DMD fibroblasts, had significantly higher levels of miR-199a-5p, a miRNA up-regulated in fibrotic conditions, compared to control exosomes, while levels in myoblast-derived exosomes were not increased. In control fibroblasts, exposure to DMD fibroblast-derived exosomes induced a myofibroblastic phenotype with increase in α-smooth actin, collagen and fibronectin transcript and protein expression, soluble collagen production and deposition, cell proliferation, and activation of Akt and ERK signaling, while exposure to control exosomes did not. Transfecting control fibroblasts or loading control exosomes with miR-199a-5p mimic or inhibitor induced opposing effects on fibrosis-related mRNAs and proteins, on collagen production and Akt and ERK pathways. The results appeared in July 04th online issue of Matrix Biol

Related Informations / Publications

- Am J Physiol Endocrinol Metab . 2018 Jul 3. Circulatory exosomal miRNA following intense exercise is unrelated to muscle and plasma miRNA abundances. D'Souza RF et al. Liggins Institute, The University of Auckland, New Zealand
Results / Comments : The uniqueness of the the exosomal miRNA response suggests its relevance as a sample pool that needs to be further explored in better understanding biological functions.
Link: Abstract
- Front Physio l. 2018 Jun 5;9:684. Phenotype-Specific Response of Circulating miRNAs Provides New Biomarkers of Slow or Fast Muscle Damage. Siracusa J et al. Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
Link: Abstrac t – Full Text

THERAPEUTIC STRATEGIES

Dynamic miRNA activity identifies therapeutic targets in trastuzumab-resistant HER2+ breast cancer

MicroRNAs (miRNA) are implicated in numerous physiologic and pathologic processes, such as the development of resistance to chemotherapy. Determining the role of miRNAs in these processes is often accomplished through measuring miRNA abundance by PCR, sequencing, or microarrays. American investigators have developed a system for the large-scale monitoring of dynamic miRNA activity, and have applied this system to identify the contribution miRNA activity to the development of trastuzumab resistance in a cell model of HER2+ breast cancer. miRNA activity measurements identified significantly different activity levels between BT474 cells (HER2+ breast cancer) and BT474R cells (HER2+ breast cancer cells selected for resistance to trastuzumab). They created a library of 32 miRNA reporter constructs, which were delivered by lentiviral transduction into cells, and miRNA activity was quantified by bioluminescence imaging
The results appeared in July 07th online issue of Biotechnol Bioeng

Related Informations / Publications

- Breast Cancer Res Trea t. 2018 May 30. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Jain S et al. Northwestern University Feinberg School of Medicine, 676 N St. Clair St. Suite 850, Chicago, IL, 60611, USA
Link : Abstract
- Oncotarget . 2018 Jun 15;9(46):27920-27928. MiR-205 as predictive biomarker and adjuvant therapeutic tool in combination with trastuzumab. Cataldo A et al. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Results / Comments : The data indicate that miR-205 could predict Trastuzumab efficacy and that its modulation might be useful as adjuvant treatment to improve the response to the drug
Link: Abstract – Full Text
- Cancer Gene Ther . 2018 Jun 21. miR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells. Yue D & Qin X, China Medical University, Shenyang, China
Results /Comments: The results suggest that the activation of miR-182 or inactivation of its target gene pathway could be used as a new method to reverse trastuzumab resistance in breast cancer
Link: Abstract

Intestinal permeability, digestive stability and oral bioavailability of dietary small RNAs

Impactful dietary RNA delivery requires improving uptake and enhancing digestive stability. In mouse feeding regimes, we have demonstrated that a plant-based ribosomal RNA (rRNA), MIR2911, is more bioavailable than synthetic MIR2911 or canonical microRNAs (miRNAs). Here mutagenesis was used to discern if MIR2911 has a distinctive sequence that aids stability and uptake. Various mutations had modest impacts while one scrambled sequence displayed significantly enhanced digestive stability, serum stability, and bioavailability. To assess if small RNA (sRNA) bioavailability in mice could be improved by increasing gut permeability, various diets, genetic backgrounds and pharmacological methods were surveyed. An intraperitoneal injection of anti-CD3 antibody enhanced gut permeability which correlated with improved uptake of the digestively stable scrambled MIR2911 variant. However, the bioavailability of canonical miRNAs was not enhanced.
The results appeared in July 06th online issue of Sci Rep

Related Informations / Publications

-Genes Nutr. 2017 Jul 7;12:17. Bioavailability of transgenic microRNAs in genetically modified plants. Yang J et al. Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030 USA
Results / Comments: This initial work suggests novel engineering strategies be employed to enhance miRNA bioavailability when attempting to use transgenic foods as a delivery platform
Link: Abstract – Full Text

RNA therapeutics in cardiovascular disease

Noncoding RNAs have been shown to exert important physiological and pathophysiological functions. Various studies suggest that modulating noncoding RNAs may provide a therapeutic option. Noncoding RNAs comprise small RNAs, mainly microRNAs, and long noncoding RNAs. MicroRNAs postranscriptionally regulate gene expression pattern by binding to the 3'untranslated region of a given target mRNA, thereby blocking protein translation or inducing its degradation. Long noncoding RNAs on the contrary have more diverse functions acting as epigenetic regulators, molecular scaffolds, or decoys. In a recent article, German researchers summarize examples of microRNAs and long noncoding RNAs, which might be promising novel targets for treatment of cardiovascular diseases, such as heart failure, acute myocardial infarction, fibrosis, as well as atherosclerosis. The review appeared in July 06th online issue of Circ Res

Related Informations / Publications

- Dis Markers . 2018 May 27;2018:2410451. A Preliminary Study of microRNA-208b after Acute Myocardial Infarction: Impact on 6-Month Survival. Alavi-Moghaddam M et al. Shahid Beheshti University of Medical Sciences, Tehran, Iran
Results / Comments : These pilot data indicate the need for a large follow-up study to confirm whether miR-208b can be used as a predictor of 6-month survival time after AMI
Link: Abstract – Full Text
-Hypertens Res. 2018 Jul 4. microRNA-21 and hypertension. Li X. Capital Medical University, 100029, Beijing, China
Link: Abstract

DISRUPTIVE TECHNOLOGIES

Exosome-mediated small RNA delivery: A novel therapeutic approach for inflammatory lung responses

Exosomes (EXOs) are a type of extracellular nanovesicles released from living cells. Accumulating evidence suggests that EXOs are involved in the pathogenesis of human diseases, including lung conditions. In recent years, the potential of EXO-mediated drug delivery has gained increasing interest. In a recent report, American investigors have investigated whether inhaled EXOs serve as an efficient and practical delivery vehicle to activate or inhibit alveolar macrophages (AMs), subsequently modulating pulmonary immune responses. They first identified the recipient cells of the inhaled EXOs, which were labeled with PKH26. They found that only lung macrophages efficiently take up intratracheally instilled EXOs in vivo . Using modified calcium chloride-mediated transformation, they manipulated small RNA molecules in serum-derived EXOs, including siRNAs, microRNA (miRNA) mimics, and miRNA inhibitors. Via intratracheal instillation, they successfully delivered siRNA and miRNA mimics or inhibitors into lung macrophages using the serum-derived EXOs as vehicles. Furthermore, EXO siRNA or miRNA molecules are functional in modulating LPS-induced lung inflammation in vivo .
The results appeared in July 10th online issue of Mol Ther

Related Informations / Publications

- J Vis Exp . 2018 Jun 15;(136). In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge. Kent OA et al, Princess Margaret Cancer Centre, University of Toronto, Canada
Results / Comments: Combining nanovector and miRNA-sponge technologies permits an effective delivery and tissue-specific miRNA inhibition in vivo
Link: Abstract
-O ncol Lett. 2018 Jun;15(6):9811-9817. Exosome-mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR-21. Jing C et al. The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
Results /Comments : The induction of miR-21 via exosomes and the activation of Akt may be mechanisms by which exosomes mediate the transfer of drug resistance
Link: Abstract – Full Text
- Methods Mol Biol . 2018;1811:49-63. Preparation of Anti-miR PNAs for Drug Development and Nanomedicine. Manicardi A et al. University of Parma, Parma, Italy
Link: Abstract

Design, synthesis and activity of light deactivatable microRNA inhibitor

miRNAs are key cellular regulators and their dysregulation is associated with many human diseases. They are usually produced locally in a spatiotemporally controlled manner to target mRNAs and regulate gene expression. Thus, developing chemical tools for manipulating miRNA with spatiotemporal precise is critical for studying miRNA. American researchers designed a strategy to control miRNA biogenesis with light controllable inhibitor targeting the pre-miRNA processing by Dicer. By conjugating two non-inhibiting units, a low affinity Dicer inhibitor and a pre-miRNA binder, through a photocleavable linker, the bifunctional molecule obtained could inhibit miRNA production. Taking advantage of the photocleavable property of the linker, the bifunctional inhibitor can be fragmented into separate non-inhibiting units and therefore be deactivated by light.
The results appeared in July 02nd online issue of Bioorg Chem

Related Informations / Publications

-J Am Chem Soc . 2017 Mar 29. Regulating miRNA-21 Biogenesis By Bifunctional Small Molecules. Yan H et al. University of New Mexico , 300 Terrace Street NE, Albuquerque, New Mexico 87131, United States
Link: Abstract

INDUSTRIAL LANDSCAPE
& agreements

Regulus announces strategic update and corporate restructuring

Regulus Therapeutics , a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs, announced on July 5th a strategic update and corporate restructuring. With the goal of extending its cash runway, Regulus has taken the following steps: recruitment activities for the RG-012 clinical program in Alport syndrome have been paused while discussions with Sanofi to potentially restructure the partnership are ongoing; preclinical research efforts will be focused on its Hepatitis B virus (HBV) programs; and a workforce reduction of approximately 60% is being implemented. These actions are anticipated to yield over $20 million of annualized savings, which are intended to extend the Company's cash runway into mid-2019.
For further information

Related Informations / Publications

-MAY 2018 : Regulus Initiates Multiple Ascending Dose Study in Healthy Volunteers of RGLS4326 for the Treatment of autosomal dominant polycystic kidney disease
Results / Comments: Initial safety and pharmacokinetic results from single ascending dose study support advancement
Link: Press Release
- J Med Virol . 2018 Jun 13. Circulating microRNA-122 levels are important predictor of HBV surface antigen seroclearance. Akuta N et al. Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Results / Comments: Understanding the complexity of the interactions among various virus- and host-related factors could potentially help in the design of new therapies that enhance HBsAg seroclearance Link: Abstract
- Int J Mol Sci . 2018 Apr 17;19(4). The Role of miRNAs in Virus-Mediated Oncogenesis. Vojtechova Z & Tachezy R, Charles University, Průmyslová 595, Vestec, CZ-25250, 128 44 Prague, Czech Republic Link: Abstract – Full Text

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