Endogenous MicroRNA Competition as a Mechanism of shRNA-Induced Cardiotoxicity.

Abstract:

:Gene knockdown using short hairpin RNAs (shRNAs) is a promising strategy for targeting dominant mutations; however, delivering too much shRNA can disrupt the processing of endogenous microRNAs (miRNAs) and lead to toxicity. Here, we sought to understand the effect that excessive shRNAs have on muscle miRNAs by treating mice with recombinant adeno-associated viral vectors (rAAVs) that produce shRNAs with 19-nt or 21-nt stem sequences. Small RNA sequencing of their muscle and liver tissues revealed that shRNA expression was highest in the heart, where mice experienced substantial cardiomyopathy when shRNAs accumulated to 51.2% ± 13.7% of total small RNAs. With the same treatment, shRNAs in other muscle tissues reached only 12.1% ± 5.0% of total small RNAs. Regardless of treatment, the predominant heart miRNAs remained relatively stable across samples. Instead, the lower-expressed miR-451, one of the few miRNAs processed independently of Dicer, changed in relation to shRNA level and toxicity. Our data suggest that a protective mechanism exists in cardiac tissue for maintaining the levels of most miRNAs in response to shRNA delivery, in contrast with what has been shown in the liver. Quantifying miRNA profiles after excessive shRNA delivery illuminates the host response to rAAV-shRNA, allowing for safer and more robust therapeutic gene knockdown.

journal_name

Mol Ther Nucleic Acids

authors

Course MM,Gudsnuk K,Desai N,Chamberlain JR,Valdmanis PN

doi

10.1016/j.omtn.2019.12.007

subject

Has Abstract

pub_date

2020-03-06 00:00:00

pages

572-580

issn

2162-2531

pii

S2162-2531(19)30402-0

journal_volume

19

pub_type

杂志文章
  • The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma.

    abstract::Hepatocellular carcinoma (HCC) is one of the most lethal human malignancies. Chemotherapeutic agents, such as sorafenib and lenvatinib, can improve the outcomes of HCC patients. Nevertheless, chemoresistance has become a major hurdle in the effective treatment of HCC. Noncoding RNAs (ncRNAs), including mircoRNAs (miRN...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章,评审

    doi:10.1016/j.omtn.2020.05.011

    authors: Wang M,Yu F,Chen X,Li P,Wang K

    更新日期:2020-09-04 00:00:00

  • miR-149-3p Regulates the Switch between Adipogenic and Osteogenic Differentiation of BMSCs by Targeting FTO.

    abstract::Bone marrow-derived mesenchymal stem cells (BMSCs) have been suggested to possess the capacity to differentiate into different cell lineages. Maintaining a balanced stem cell differentiation program is crucial to the bone microenvironment and bone development. MicroRNAs (miRNAs) have played a critical role in regulati...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.06.023

    authors: Li Y,Yang F,Gao M,Gong R,Jin M,Liu T,Sun Y,Fu Y,Huang Q,Zhang W,Liu S,Yu M,Yan G,Feng C,He M,Zhang L,Ding F,Ma W,Bi Z,Xu C,Yuan Y,Cai B,Yang L

    更新日期:2019-09-06 00:00:00

  • Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells.

    abstract::Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV) cell suicide system into ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.03.004

    authors: Ingemarsdotter CK,Poddar S,Mercier S,Patzel V,Lever AML

    更新日期:2017-06-16 00:00:00

  • An innovative data analysis strategy for accurate next-generation sequencing detection of tumor mitochondrial DNA mutations.

    abstract::Next-generation sequencing technology has been commonly applied to detect mitochondrial DNA (mtDNA) mutations, which are reported to be strongly associated with cancers. However, several key challenges still exist regarding bioinformatics analysis of mtDNA sequencing data that greatly affect the detection accuracy of ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.11.002

    authors: Guo S,Zhou K,Yuan Q,Su L,Liu Y,Ji X,Gu X,Guo X,Xing J

    更新日期:2020-11-11 00:00:00

  • Binding and Structural Properties of DNA Aptamers with VEGF-A-Mimic Activity.

    abstract::Vascular endothelial growth factors (VEGFs) are hypoxia-inducible secreted proteins to promote angiogenesis, in which VEGF-A is an important molecule that binds and activates VEGF receptor-1 (VEGFR-1) and VEGFR-2. In this study, two DNA aptamers, Apt01 and Apt02, were successfully isolated by alternating consecutive s...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.12.034

    authors: Yoshitomi T,Hayashi M,Oguro T,Kimura K,Wayama F,Furusho H,Yoshimoto K

    更新日期:2020-03-06 00:00:00

  • Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers.

    abstract::Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the three most common receptors present on other subtypes, leaving it unsusceptible to current targeted or hormonal therapies. In this study, we introduce an alternative treatment strategy for TNBC that exploits its...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.06.003

    authors: Valcourt DM,Day ES

    更新日期:2020-09-04 00:00:00

  • PAK1 Promotes the Proliferation and Inhibits Apoptosis of Human Spermatogonial Stem Cells via PDK1/KDR/ZNF367 and ERK1/2 and AKT Pathways.

    abstract::Spermatogonial stem cells (SSCs) have significant applications in reproductive and regenerative medicine. However, nothing is known about genes in mediating human SSCs. Here we have explored for the first time the function and mechanism of P21-activated kinase 1 (PAK1) in regulating the proliferation and apoptosis of ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.06.006

    authors: Fu H,Zhang W,Yuan Q,Niu M,Zhou F,Qiu Q,Mao G,Wang H,Wen L,Sun M,Li Z,He Z

    更新日期:2018-09-07 00:00:00

  • Dual Mechanisms of Action of Self-Delivering, Anti-HIV-1 FANA Oligonucleotides as a Potential New Approach to HIV Therapy.

    abstract::Currently, the most effective and durable therapeutic option for HIV-1 infection is combination antiretroviral therapy (cART). Although cART is powerful and can delay viral evolution of drug resistance for decades, it is associated with limitations, including an inability to eradicate the virus and a potential for adv...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.07.001

    authors: Takahashi M,Li H,Zhou J,Chomchan P,Aishwarya V,Damha MJ,Rossi JJ

    更新日期:2019-09-06 00:00:00

  • Histone-targeted Polyplexes Avoid Endosomal Escape and Enter the Nucleus During Postmitotic Redistribution of ER Membranes.

    abstract::Nonviral gene delivery is a promising therapeutic approach because of its safety and controllability, yet limited gene transfer efficacy is a common issue. Most nonviral strategies rely upon endosomal escape designs; however, endosomal escape is often uncorrelated with improved gene transfer and membranolytic structur...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2015.2

    authors: Ross NL,Munsell EV,Sabanayagam C,Sullivan MO

    更新日期:2015-02-10 00:00:00

  • RNAm5CPred: Prediction of RNA 5-Methylcytosine Sites Based on Three Different Kinds of Nucleotide Composition.

    abstract::5-methylcytosine (m5C) is one of the most common and abundant post-transcriptional modifications (PTCMs) in RNA. Recent studies showed that m5C plays important roles in many biological functions such as RNA metabolism and cell fate decision. Because most experimental methods that determine m5C sites across the transcr...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.10.008

    authors: Fang T,Zhang Z,Sun R,Zhu L,He J,Huang B,Xiong Y,Zhu X

    更新日期:2019-12-06 00:00:00

  • miR-582-3p and miR-582-5p Suppress Prostate Cancer Metastasis to Bone by Repressing TGF-β Signaling.

    abstract::A number of studies have reported that aberrant expression of microRNAs (miRNAs) closely correlates with the bone metastasis of prostate cancer (PCa). However, clinical significance and functional roles of both strands of a single miRNA in bone metastasis of PCa remain undefined. Here, we reported that miR-582-3p and ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.01.004

    authors: Huang S,Zou C,Tang Y,Wa Q,Peng X,Chen X,Yang C,Ren D,Huang Y,Liao Z,Huang S,Zou X,Pan J

    更新日期:2019-06-07 00:00:00

  • Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.

    abstract::We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol-conjugated siRNA was effective and safe for RNA interference-mediated gene silencing in vivo. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligon...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2014.72

    authors: Nishina T,Numata J,Nishina K,Yoshida-Tanaka K,Nitta K,Piao W,Iwata R,Ito S,Kuwahara H,Wada T,Mizusawa H,Yokota T

    更新日期:2015-01-13 00:00:00

  • Prevention of Asthma Exacerbation in a Mouse Model by Simultaneous Inhibition of NF-κB and STAT6 Activation Using a Chimeric Decoy Strategy.

    abstract::Transactivation of inflammatory and immune mediators in asthma is tightly regulated by nuclear factor κB (NF-κB) and signal transducer and activator of transcription 6 (STAT6). Therefore, we investigated the efficacy of simultaneous inhibition of NF-κB and STAT6 using a chimeric decoy strategy to prevent asthma exacer...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2017.12.005

    authors: Miyake T,Miyake T,Sakaguchi M,Nankai H,Nakazawa T,Morishita R

    更新日期:2018-03-02 00:00:00

  • Compatibility and Fidelity of Mirror-Image Thymidine in Transcription Events by T7 RNA Polymerase.

    abstract::Due to highly enzymatic d-stereoselectivity, l-nucleotides (l-2'-deoxynucleoside 5'-triphosphates [l-dNTPs]) are not natural targets of polymerases. In this study, we synthesized series of l-thymidine (l-T)-modified DNA strands and evaluated the processivity of nucleotide incorporation for transcription by T7 RNA poly...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.06.023

    authors: Liu Q,Ke Y,Kan Y,Tang X,Li X,He Y,Wu L

    更新日期:2020-09-04 00:00:00

  • Implications of Newly Identified Brain eQTL Genes and Their Interactors in Schizophrenia.

    abstract::Schizophrenia (SCZ) is a devastating genetic mental disorder. Identification of the SCZ risk genes in brains is helpful to understand this disease. Thus, we first used the minimum Redundancy-Maximum Relevance (mRMR) approach to integrate the genome-wide sequence analysis results on SCZ and the expression quantitative ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.05.026

    authors: Cai L,Huang T,Su J,Zhang X,Chen W,Zhang F,He L,Chou KC

    更新日期:2018-09-07 00:00:00

  • Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells.

    abstract::Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used clinically as target therapies for lung cancer patients, but the occurrence of acquired drug resistance limits their efficacy. Nicotinamide N-methyltransferase (NNMT), a cancer-associated metabolic enzyme, is commonly overexpressed in var...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.03.011

    authors: Bach DH,Kim D,Bae SY,Kim WK,Hong JY,Lee HJ,Rajasekaran N,Kwon S,Fan Y,Luu TT,Shin YK,Lee J,Lee SK

    更新日期:2018-06-01 00:00:00

  • Expanding the Repertoire of Target Sites for Zinc Finger Nuclease-mediated Genome Modification.

    abstract::Recent studies have shown that zinc finger nucleases (ZFNs) are powerful reagents for making site-specific genomic modifications. The generic structure of these enzymes includes a ZF DNA-binding domain and nuclease domain (Fn) are separated by an amino acid "linker" and cut genomic DNA at sites that have a generic str...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2013.13

    authors: Wilson KA,McEwen AE,Pruett-Miller SM,Zhang J,Kildebeck EJ,Porteus MH

    更新日期:2013-04-30 00:00:00

  • Menin Coordinates C/EBPβ-Mediated TGF-β Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer.

    abstract::Menin displays either tumor suppression or promotion functions in a context-dependent manner. Previously, we proposed that Menin acts as a tumor suppressor by inhibiting cell growth in pancreatic ductal adenocarcinoma (PDAC), whereas the relationship between the Menin expression and overall survival rate of PDAC patie...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.08.013

    authors: Cheng P,Chen Y,He TL,Wang C,Guo SW,Hu H,Ni CM,Jin G,Zhang YJ

    更新日期:2019-12-06 00:00:00

  • Two interconvertible folds modulate the activity of a DNA aptamer against transferrin receptor.

    abstract::Thanks to their ability to recognize biomolecular targets with high affinity and specificity, nucleic acid aptamers are increasingly investigated as diagnostic and therapeutic tools, particularly when their targets are cell-surface receptors. Here, we investigate the relationship between the folding of an anti-mouse t...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2013.71

    authors: Porciani D,Signore G,Marchetti L,Mereghetti P,Nifosì R,Beltram F

    更新日期:2014-01-28 00:00:00

  • The Bipartite Network Projection-Recommended Algorithm for Predicting Long Non-coding RNA-Protein Interactions.

    abstract::With the development of science and biotechnology, many evidences show that ncRNAs play an important role in the development of important biological processes, especially in chromatin modification, cell differentiation and proliferation, RNA progressing, human diseases, etc. Moreover, lncRNAs account for the majority ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2018.09.020

    authors: Zhao Q,Yu H,Ming Z,Hu H,Ren G,Liu H

    更新日期:2018-12-07 00:00:00

  • Identification and Characterization of an eIF4e DNA Aptamer That Inhibits Proliferation With High Throughput Sequencing.

    abstract::Development of DNA aptamer screens that are both simple and informative can increase the success rate of DNA aptamer selection and induce greater adoption. High eIF4e levels contribute to malignancies, thus eIF4e presents itself as a valuable target for DNA aptamer-based inhibition screen. Here, we demonstrate a metho...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2014.70

    authors: Guo WM,Kong KW,Brown CJ,Quah ST,Yeo HL,Hoon S,Seow Y

    更新日期:2014-12-16 00:00:00

  • Schizandrin A Protects Human Retinal Pigment Epithelial Cell Line ARPE-19 against HG-Induced Cell Injury by Regulation of miR-145.

    abstract::Diabetic retinopathy (DR) is a serious complication of diabetes, which is the main cause of blindness among adults. Traditional Chinese medicines (TCMs) have been proven to delay the development of DR. Nonetheless, the effect of Schizandrin A (SchA) on DR remains uninvestigated. The present study aimed to probe the pr...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2019.10.026

    authors: Dong Y,Qian C,Wan G,Yan P,Liang S,Wang J

    更新日期:2020-03-06 00:00:00

  • In Vivo Selection Against Human Colorectal Cancer Xenografts Identifies an Aptamer That Targets RNA Helicase Protein DHX9.

    abstract::The ability to selectively target disease-related tissues with molecules is critical to the design of effective therapeutic and diagnostic reagents. Recognizing the differences between the in vivo environment and in vitro conditions, we employed an in vivo selection strategy to identify RNA aptamers (targeting motifs)...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2016.27

    authors: Mi J,Ray P,Liu J,Kuan CT,Xu J,Hsu D,Sullenger BA,White RR,Clary BM

    更新日期:2016-04-26 00:00:00

  • Combination of microRNA-21 and microRNA-146a Attenuates Cardiac Dysfunction and Apoptosis During Acute Myocardial Infarction in Mice.

    abstract::Recent studies have revealed the cytoprotective roles of microRNAs (miRNAs) miR-21 and miR-146a against ischemic cardiac injuries. While these studies investigated each of these miRNAs as an independent individual factor, our previous study has suggested the possible interaction between these two miRNAs. The present s...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2016.12

    authors: Huang W,Tian SS,Hang PZ,Sun C,Guo J,Du ZM

    更新日期:2016-03-15 00:00:00

  • RNA-Guided CRISPR-Cas9 System-Mediated Engineering of Acute Myeloid Leukemia Mutations.

    abstract::Current acute myeloid leukemia (AML) disease models face severe limitations because most of them induce un-physiological gene expressions that do not represent conditions in AML patients and/or depend on external promoters for regulation of gene expression/repression. Furthermore, many AML models are based on reciproc...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2016.12.012

    authors: Brabetz O,Alla V,Angenendt L,Schliemann C,Berdel WE,Arteaga MF,Mikesch JH

    更新日期:2017-03-17 00:00:00

  • Mir-34: a new weapon against cancer?

    abstract::The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. I...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章,评审

    doi:10.1038/mtna.2014.47

    authors: Misso G,Di Martino MT,De Rosa G,Farooqi AA,Lombardi A,Campani V,Zarone MR,Gullà A,Tagliaferri P,Tassone P,Caraglia M

    更新日期:2014-09-23 00:00:00

  • A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy.

    abstract::Recent reports underscore the unparalleled potential of antisense-oligonucleotide (ASO)-based approaches to ameliorate various pathological conditions. However, in vivo studies validating the effectiveness of a short ASO (<10-mer) in the context of a human disease have not been performed. One disease with proven amena...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2014.23

    authors: Keil JM,Seo J,Howell MD,Hsu WH,Singh RN,DiDonato CJ

    更新日期:2014-07-08 00:00:00

  • Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers.

    abstract::Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a num...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1038/mtna.2015.11

    authors: Prodeus A,Abdul-Wahid A,Fischer NW,Huang EH,Cydzik M,Gariépy J

    更新日期:2015-04-28 00:00:00

  • circHMCU Promotes Proliferation and Metastasis of Breast Cancer by Sponging the let-7 Family.

    abstract::Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMC...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.03.014

    authors: Song X,Liang Y,Sang Y,Li Y,Zhang H,Chen B,Du L,Liu Y,Wang L,Zhao W,Ma T,Wang C,Yang Q

    更新日期:2020-06-05 00:00:00

  • Identification of Novel Tumor-Microenvironment-Regulating Factor That Facilitates Tumor Immune Infiltration in Colon Cancer.

    abstract::Colon cancer is one of the most common malignancies causing death worldwide. It is well known that the cells of the tumor microenvironment contribute to the progression and prognosis of colon cancer. However, the gene alterations and potential remodeling mechanisms in the tumor microenvironment of colon cancer remain ...

    journal_title:Molecular therapy. Nucleic acids

    pub_type: 杂志文章

    doi:10.1016/j.omtn.2020.08.029

    authors: Wang Y,Wang Y,Xu C,Liu Y,Huang Z

    更新日期:2020-08-29 00:00:00