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Delivery of Modified mRNA in a Myocardial Infarction Mouse Model
Published on: June 11, 2020
Functionalized dendrimer-based delivery of angiotensin type 1 receptor siRNA for preserving cardiac function
Jie Liu1, Catherine Gu, E Bernadette Cabigas
1Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.
Insights
Researchers developed novel dendrimeric materials for siRNA delivery to treat cardiovascular disease. This new method effectively silenced the Angiotensin II type 1 receptor (AT1R) in a rat model, improving cardiac function after injury.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Gene Therapy
Background:
- Cardiovascular disease (CVD) is a leading global cause of mortality.
- Inflammatory gene upregulation significantly contributes to CVD pathology.
- Efficient RNA interference (RNAi) delivery systems are crucial for treating CVDs but are lacking.
Purpose of the Study:
- To develop and evaluate novel tadpole dendrimeric materials for siRNA delivery in cardiovascular disease.
- To target the Angiotensin II (Ang II) type 1 receptor (AT1R) for gene silencing in an ischemia-reperfusion (IR) injury model.
Main Methods:
- Synthesis of three tadpole dendrimers for siRNA delivery.
- In vitro assessment of siRNA-loaded dendrimer efficacy in down-regulating AT1R expression in cardiomyocytes.
- In vivo evaluation of dendrimer-siRNA complex in a rat IR injury model to assess cardiac function and AT1R levels.
Main Results:
- An oligo-arginine conjugated dendrimer effectively delivered siRNA, leading to significant AT1R down-regulation in cardiomyocytes in vitro.
- In vivo administration of the dendrimeric material prevented IR-induced AT1R upregulation.
- Cardiac function recovery was significantly improved in the IR injury model treated with dendrimer-siRNA compared to controls.
Conclusions:
- Tadpole dendrimeric materials show promise as efficient siRNA delivery vehicles for cardiovascular applications.
- This approach offers a potential therapeutic strategy for treating cardiac dysfunction following IR injury.
- The developed dendrimers may serve as an alternative to traditional AT1R blockade therapies.
Abstract:
Cardiovascular disease (CVD) is the leading cause of death throughout the world and much pathology is associated with upregulation of inflammatory genes. Gene silencing using RNA interference is a powerful tool in regulating gene expression, but its application in CVDs has been prevented by the lack of efficient delivery systems. We report here the development of tadpole dendrimeric materials for siRNA delivery in a rat ischemia-reperfusion (IR) model. Angiotensin II (Ang II) type 1 receptor (AT1R), the major receptor that mediates most adverse effects of Ang II, was chosen to be the silencing targeting. Among the three tadpole dendrimers synthesized, the oligo-arginine conjugated dendrimer loaded with siRNA demonstrated effective down-regulation in AT1R expression in cardiomyocytes in vitro. When the dendrimeric material was applied in vivo, the siRNA delivery prevented the increase in AT1R levels and significantly improved cardiac function recovery compared to saline injection or empty dendrimer treated groups after IR injury. These experiments demonstrate a potential treatment for dysfunction caused by IR injury and may represent an alternative to AT1R blockade.
