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Status |
Public on Nov 19, 2022 |
Title |
Hydrogel-based intramyocardial delivery of antimiR-195 after ischemia-reperfusion injury [UPyPEG_IR] |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Background MicroRNAs are potent regulators of biology and disease. The miR-15 family has been shown to regulate cardiomyocyte proliferation and antimiR-based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. pH-responsive injectable hydrogels serve as a sustained-release drug delivery depot and could potentially be used to improve cardiac efficacy of antimiR therapeutics.
Objective Examine whether hydrogel can improve local delivery of antimiR-195 in ischemic hearts to increase cardiac efficacy and limit off-target effects.
Methods Study the effect of intramyocardial injections of hydrogel-formulated antimiR-195 under both baseline conditions and after ischemic injury.
Results Intracardiac injections of UPy-PEG induced a transient inflammatory response that was no longer present 7 days post-injection. In vitro experiments showed that antimiR-195 was released from the gel, and induced microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR-195 in UPy-PEG enhanced cardiac target de-repression compared to PBS-dissolved antimiR-195, despite a low cardiac retention. After ischemic injury, this translated into a greater therapeutic effect by increasing both target de-repression and cardiomyocyte proliferation.
Conclusions UPy-PEG can be used as a cardiac delivery vehicle of antimiRs and intramyocardial injection of UPy-PEG formulated antimiR-195 is sufficient to improve cardiac efficacy of antimiR-195. Follow up experiments in large animals will enable us to assess the true added value of using UPy-PEG to increase cardiac exposure of antimiR therapies.
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Overall design |
Healthy mice were subjected to cardiac ischemia-reperfusion injury (anesthesia, intubation, opening of thorax, ligation of LAD, reperfusion and intramyocardial injection (2x10µl) of Upy-PEG hydrogel; either with no drug or with antimiR-195. Hearts were harvested for RNA-analysis 3 days after injury injection. There are 2 groups (Upy-PEG, UPy-PEG-antimiR) with 4 samples per group
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Contributor(s) |
Eding JE, Vigil Garcia M, Vink M, Demkes CJ, Versteeg D, Kooijman L, Bakker MH, Schotman MJ, Dankers PY, van Rooij E |
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Submission date |
Nov 19, 2019 |
Last update date |
Nov 21, 2022 |
Contact name |
Eva van Rooij |
E-mail(s) |
e.vanrooij@hubrecht.eu
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Organization name |
Hubrecht Institute
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Lab |
Eva van Rooij
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Street address |
Uppsalalaan 8
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City |
Utrecht |
ZIP/Postal code |
3531KC |
Country |
Netherlands |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (8)
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This SubSeries is part of SuperSeries: |
GSE140661 |
Hydrogel-based intramyocardial delivery of antimiR-195 |
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Relations |
BioProject |
PRJNA590477 |
SRA |
SRP230620 |