Preclinical development of a miR-132 inhibitor for heart failure treatment.

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Tytuł:: Preclinical development of a miR-132 inhibitor for heart failure treatment.
Autorzy:: Foinquinos A; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Batkai S; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.; CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany.
Genschel C; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.; CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany.
Viereck J; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.; CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany.
Rump S; CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany.
Gyöngyösi M; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Traxler D; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Riesenhuber M; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Spannbauer A; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Lukovic D; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Weber N; Institute of Molecular and Cell Physiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Zlabinger K; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Hašimbegović E; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Winkler J; Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Fiedler J; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Dangwal S; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Fischer M; Institute for Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
de la Roche J; Institute for Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Wojciechowski D; Institute for Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Kraft T; Institute of Molecular and Cell Physiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Garamvölgyi R; Department of Diagnostic Imaging and Oncoradiology, University of Kaposvár, Guba S. Street 40, Kaposvár, 7400, Hungary.
Neitzel S; Axolabs GmbH, Fritz-Hornschuch-Straße 9, 95326, Kulmbach, Germany.
Chatterjee S; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Yin X; The James Black Centre, King's College, University of London, 125 Coldharbour Lane, London, SE5 9NU, UK.
Bär C; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Mayr M; The James Black Centre, King's College, University of London, 125 Coldharbour Lane, London, SE5 9NU, UK.
Xiao K; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Thum T; Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. .; CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, 30625, Hannover, Germany. .; REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. .
Źródło:: Nature communications [Nat Commun] 2020 Jan 31; Vol. 11 (1), pp. 633. Date of Electronic Publication: 2020 Jan 31.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Genetic Therapy/*methods
Heart Failure/*genetics
Heart Failure/*therapy
MicroRNAs/*genetics
Oligonucleotides, Antisense/*genetics
Animals ; Drug Evaluation, Preclinical ; Female ; Gene Expression Regulation ; Heart Failure/metabolism ; Humans ; MicroRNAs/metabolism ; Myocytes, Cardiac/metabolism ; Oligonucleotides, Antisense/metabolism ; Oligonucleotides, Antisense/pharmacokinetics ; Swine
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Grant Information:: CH/16/3/32406 United Kingdom BHF_ British Heart Foundation; RG/16/14/32397 United Kingdom BHF_ British Heart Foundation
Substance Nomenclature:: 0 (MicroRNAs)
0 (Oligonucleotides, Antisense)
Entry Date(s):: Date Created: 20200202 Date Completed: 20200511 Latest Revision: 20220323
Update Code:: 20240105
PubMed Central ID:: PMC6994493
DOI:: 10.1038/s41467-020-14349-2
PMID:: 32005803
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Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

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