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Article ; Online: Development of a Mechanism-Based Next-Generation Therapeutic for Heart Failure Derived From the Dark Genome.

Viereck, Janika / Thum, Thomas

JACC. Basic to translational science

2023 Volume 8, Issue 12, Page(s) 1595–1598

Abstract: The ability of nucleic acids for intramolecular interactions opens manifold opportunities for novel medicines that have the potential to treat intractable human disorders, including heart disease. In this context, microRNAs have been identified as ... ...

Abstract	The ability of nucleic acids for intramolecular interactions opens manifold opportunities for novel medicines that have the potential to treat intractable human disorders, including heart disease. In this context, microRNAs have been identified as pleiotropic regulators of disease pathways and consequently as powerful therapeutic targets. With antisense oligonucleotides novel drug modalities are available to specifically inhibit as well as correct derailed microRNAs including pathological downstream pathways potentially restoring hallmarks of disease. However, only a handful of microRNA-targeting drugs underwent clinical testing so far, and none in the cardiovascular field. In this paper, the authors introduce the first-ever microRNA-based therapy that entered clinical trials in heart disease and present the previous development from target identification to first-in-human studies.
Language	English
Publishing date	2023-12-26
Publishing country	United States
Document type	Journal Article
ISSN	2452-302X
ISSN (online)	2452-302X
DOI	10.1016/j.jacbts.2023.09.006
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Article ; Online: Circulating Noncoding RNAs as Biomarkers of Cardiovascular Disease and Injury.

Viereck, Janika / Thum, Thomas

Circulation research

2017 Volume 120, Issue 2, Page(s) 381–399

Abstract: The discovery of thousands of noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well as their organization and regulation. Accumulating evidence on aberrantly regulated ncRNAs, including short microRNAs, long ... ...

Abstract	The discovery of thousands of noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well as their organization and regulation. Accumulating evidence on aberrantly regulated ncRNAs, including short microRNAs, long ncRNAs and circular RNAs, across various heart diseases indicates that ncRNAs are critical contributors to cardiovascular pathophysiology. In addition, ncRNAs are released into the circulation where they are present in concentration levels that differ between healthy subjects and diseased patients. Although little is known about the origin and function of such circulating ncRNAs, these molecules are increasingly recognized as noninvasive and readily accessible biomarker for risk stratification, diagnosis and prognosis of cardiac injury, and multiple forms of cardiovascular disease. In this review, we summarize recent findings on biological characteristics of circulating ncRNAs and highlight their value as potential biomarker in selected pathologies of cardiovascular disease.
MeSH term(s)	Animals ; Biomarkers/blood ; Cardiovascular Diseases/blood ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/genetics ; Humans ; MicroRNAs/blood ; MicroRNAs/genetics ; RNA, Long Noncoding/blood ; RNA, Long Noncoding/genetics ; RNA, Untranslated/blood ; RNA, Untranslated/genetics
Chemical Substances	Biomarkers ; MicroRNAs ; RNA, Long Noncoding ; RNA, Untranslated
Language	English
Publishing date	2017-01-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.116.308434
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Article ; Online: Long Noncoding RNAs in Pathological Cardiac Remodeling.

Viereck, Janika / Thum, Thomas

Circulation research

2017 Volume 120, Issue 2, Page(s) 262–264

Abstract: A novel long noncoding RNA Chaer acts as noncoding epigenetic regulator at the onset of cardiac hypertrophy and enables an improved understanding about the complex mechanisms in cardiovascular disease. ...

Abstract	A novel long noncoding RNA Chaer acts as noncoding epigenetic regulator at the onset of cardiac hypertrophy and enables an improved understanding about the complex mechanisms in cardiovascular disease.
MeSH term(s)	Animals ; Cardiomegaly/diagnosis ; Cardiomegaly/genetics ; Cardiomegaly/physiopathology ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/physiopathology ; Humans ; RNA, Long Noncoding/genetics ; Ventricular Remodeling/genetics
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2017-01-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.116.310174
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Article ; Online: Efficacy and safety of CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: Rationale and design of the HF-REVERT trial.

Bauersachs, Johann / Solomon, Scott D / Anker, Stefan D / Antorrena-Miranda, Isabel / Batkai, Sandor / Viereck, Janika / Rump, Steffen / Filippatos, Gerasimos / Granzer, Ulrich / Ponikowski, Piotr / de Boer, Rudolf A / Vardeny, Orly / Hauke, Wilfried / Thum, Thomas

European journal of heart failure

2024

Abstract: Aim: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, ... ...

Abstract	Aim: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period. Conclusion: The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1483672-5
ISSN	1879-0844 ; 1388-9842
ISSN (online)	1879-0844
ISSN	1388-9842
DOI	10.1002/ejhf.3139
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Article: Structural and functional characterization of the Curli adaptor protein CsgF

Schubeis, Tobias / Spehr, Johannes / Viereck, Janika / Köpping, Laura / Nagaraj, Madhu / Ahmed, Mumdooh / Ritter, Christiane

FEBS letters. 2018 Mar., v. 592, no. 6

2018

Abstract: Curli are functional amyloids that form a major part of the biofilm produced by many enterobacteriaceae. A multiprotein system around the outer membrane protein CsgG is in charge of the export and controlled propagation of the main Curli subunits, CsgA ... ...

Abstract	Curli are functional amyloids that form a major part of the biofilm produced by many enterobacteriaceae. A multiprotein system around the outer membrane protein CsgG is in charge of the export and controlled propagation of the main Curli subunits, CsgA and CsgB. CsgF is essential for the linkage of the main amyloid‐forming proteins to the cell surface. Here, we present a profound biochemical and biophysical characterization of recombinant CsgF, highlighted by a solution NMR structure of CsgF in the presence of dihexanoylphosphocholine micelles. Interestingly, CsgF contains large unstructured domains and does not show a globular fold. The data presented shed new light on the molecular mechanism of Curli amyloid surface attachment.
Keywords	Enterobacteriaceae ; amyloid ; biofilm ; exports ; micelles ; outer membrane proteins
Language	English
Dates of publication	2018-03
Size	p. 1020-1029.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	LETTER
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13002
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Article ; Online: Long noncoding RNAs as inducers and terminators of vascular development.

Viereck, Janika / Kumarswamy, Regalla / Thum, Thomas

Circulation

2015 Volume 131, Issue 14, Page(s) 1236–1238

MeSH term(s)	Animals ; Cardiovascular System/growth & development ; Endothelial Cells/chemistry ; Gene Expression Regulation, Developmental/genetics ; Humans ; Myocytes, Cardiac/chemistry ; Pluripotent Stem Cells/chemistry ; RNA, Long Noncoding/isolation & purification ; Vertebrates/genetics
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2015-04-07
Publishing country	United States
Document type	Comment ; Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.115.015775
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Article ; Online: AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes.

Rode, Laura / Bär, Christian / Groß, Sonja / Rossi, Axel / Meumann, Nadja / Viereck, Janika / Abbas, Naisam / Xiao, Ke / Riedel, Isabelle / Gietz, Anika / Zimmer, Karina / Odenthal, Margarete / Büning, Hildegard / Thum, Thomas

Molecular therapy : the journal of the American Society of Gene Therapy

2022 Volume 30, Issue 12, Page(s) 3601–3618

Abstract: AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. We identified two AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, by in vivo ... ...

Abstract	AAV vectors are promising delivery tools for human gene therapy. However, broad tissue tropism and pre-existing immunity against natural serotypes limit their clinical use. We identified two AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, by in vivo AAV2 peptide display library screening in a murine model of pressure overload-induced cardiac hypertrophy. Both variants showed significantly improved efficacy in in vivo cardiomyocyte transduction compared with the parental serotype AAV2 as indicated by a higher number of AAV vector episomes in the nucleus and significant improved transduction efficiency. Both variants also outcompeted the reference serotype AAV9 regarding cardiomyocyte tropism, reaching comparable cardiac transduction efficiencies accompanied with liver de-targeting and decreased transduction efficiency of non-cardiac cells. Capsid modification influenced immunogenicity as sera of mice treated with AAV2-THGTPAD and AAV2-NLPGSGD demonstrated a poor neutralization capacity for the parental serotype and the novel variants. In a therapeutic setting, using the long non-coding RNA H19 in low vector dose conditions, novel AAV variants mediated superior anti-hypertrophic effects and revealed a further improved target-to-noise ratio, i.e., cardiomyocyte tropism. In conclusion, AAV2-THGTPAD and AAV2-NLPGSGD are promising novel tools for cardiac-directed gene therapy outperforming AAV9 regarding the specificity and therapeutic efficiency of in vivo cardiomyocyte transduction.
MeSH term(s)	Animals ; Humans ; Mice ; RNA, Long Noncoding ; Myocytes, Cardiac ; Tropism ; Capsid
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2022-07-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2022.07.003
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Article ; Online: miR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury.

Jansing, Johanna Christine / Fiedler, Jan / Pich, Andreas / Viereck, Janika / Thum, Thomas / Mühlfeld, Christian / Brandenberger, Christina

International journal of molecular sciences

2020 Volume 21, Issue 3

Abstract: Acute lung injury (ALI) is characterized by enhanced permeability of the air-blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 ... ...

Abstract	Acute lung injury (ALI) is characterized by enhanced permeability of the air-blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (
MeSH term(s)	Acute Lung Injury/etiology ; Acute Lung Injury/metabolism ; Acute Lung Injury/pathology ; Acute Lung Injury/physiopathology ; Airway Remodeling/genetics ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/ultrastructure ; Animals ; Chromatography, Liquid ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Disease Susceptibility ; Gene Expression Profiling ; Male ; Mass Spectrometry ; Mice ; Mice, Knockout ; MicroRNAs/genetics ; Pulmonary Alveoli/metabolism ; Pulmonary Alveoli/pathology ; Pulmonary Alveoli/ultrastructure ; RAW 264.7 Cells ; Respiratory Function Tests ; Signal Transduction
Chemical Substances	Cytokines ; MIRN21 microRNA, mouse ; MicroRNAs
Language	English
Publishing date	2020-01-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21030822
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Article ; Online: Structural and functional characterization of the Curli adaptor protein CsgF.

Schubeis, Tobias / Spehr, Johannes / Viereck, Janika / Köpping, Laura / Nagaraj, Madhu / Ahmed, Mumdooh / Ritter, Christiane

FEBS letters

2018 Volume 592, Issue 6, Page(s) 1020–1029

Abstract	Curli are functional amyloids that form a major part of the biofilm produced by many enterobacteriaceae. A multiprotein system around the outer membrane protein CsgG is in charge of the export and controlled propagation of the main Curli subunits, CsgA and CsgB. CsgF is essential for the linkage of the main amyloid-forming proteins to the cell surface. Here, we present a profound biochemical and biophysical characterization of recombinant CsgF, highlighted by a solution NMR structure of CsgF in the presence of dihexanoylphosphocholine micelles. Interestingly, CsgF contains large unstructured domains and does not show a globular fold. The data presented shed new light on the molecular mechanism of Curli amyloid surface attachment.
MeSH term(s)	Escherichia coli/chemistry ; Escherichia coli/genetics ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/genetics ; Nuclear Magnetic Resonance, Biomolecular ; Protein Domains ; Protein Folding ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics
Chemical Substances	Escherichia coli Proteins ; Recombinant Proteins
Language	English
Publishing date	2018-02-21
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13002
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Article ; Online: Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches.

Beermann, Julia / Piccoli, Maria-Teresa / Viereck, Janika / Thum, Thomas

Physiological reviews

2016 Volume 96, Issue 4, Page(s) 1297–1325

Abstract: Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs (miRNA) and long non-coding RNAs (lncRNA), as well as ... ...

Abstract	Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs (miRNA) and long non-coding RNAs (lncRNA), as well as circular RNAs (circRNA) consisting of a closed continuous loop. This review guides the reader through important aspects of non-coding RNA biology. This includes their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system). We specifically focus on non-coding RNAs as potential therapeutic targets and diagnostic biomarkers.
MeSH term(s)	Biomarkers/metabolism ; Humans ; MicroRNAs/physiology ; RNA/physiology ; RNA, Long Noncoding/physiology
Chemical Substances	Biomarkers ; MicroRNAs ; RNA, Long Noncoding ; RNA, circular ; RNA (63231-63-0)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	209902-0
ISSN	1522-1210 ; 0031-9333
ISSN (online)	1522-1210
ISSN	0031-9333
DOI	10.1152/physrev.00041.2015
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