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Delivery of Modified mRNA in a Myocardial Infarction Mouse Model
Published on: June 11, 2020
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Immunotherapy for Infarcts: In Vivo Postinfarction Macrophage Modulation Using Intramyocardial Microparticle Delivery
Jun Luo1, Matthew S Weaver1, Timothy P Fitzgibbons2
1Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Bioresearch Open Access
|December 30, 2020
Summary
Directly injecting small interfering RNA (siRNA)-loaded particles into the heart after myocardial infarction reduces inflammatory gene expression. This novel therapeutic approach targets cardiac macrophages for improved infarct healing.
Area of Science:
- Cardiovascular Biology
- Immunology
- Regenerative Medicine
Background:
- Myocardial infarction triggers an innate immune response involving myeloid cells that influences ventricular repair.
- Modulating this immune response presents a potential strategy for enhancing infarct healing.
Purpose of the Study:
- To pilot the use of glucan-encapsulated RNA (siRNA)-containing particles (GeRPs) for targeted delivery of therapeutics to cardiac macrophages post-myocardial infarction.
- To assess the efficacy of intramyocardial GeRP injection in modulating the inflammatory and reparative microenvironment of the infarct.
Main Methods:
- GeRPs encapsulating siRNA targeting Map4k4 were administered via one-time intramyocardial injection immediately after acute myocardial infarction in mice.
- Cardiac macrophages were confirmed to phagocytose GeRPs with minimal systemic spread.
- Gene expression (quantitative PCR), protein levels (flow cytometry), and tissue histology were analyzed at 3 and 7 days post-injection.
Main Results:
- Intrainfarct GeRP injections significantly reduced transcripts for Map4k4, IL-1β, and TNF-α by 69-89% at 3 days compared to vehicle controls.
- Expression of key matrix remodeling factors, including MCP-1, TGF-β, and CTGF, was also decreased.
- Suppression of several key genes, including Map4k4, IL-1β, TGF-β, and CTGF, persisted up to 7 days post-injection.
Conclusions:
- Direct intramyocardial GeRP injection is a feasible and potentially translatable platform for localized in vivo RNA delivery.
- This approach enables selective immunomodulation of intracardiac macrophages within the infarct microenvironment.
- Targeted delivery of siRNA via GeRPs offers a novel strategy to improve infarct healing after myocardial infarction.
