Synthetic MicroRNAs Stimulate Cardiac Repair

Zangi, Lior; Hajjar, Roger J.

doi:10.1161/circresaha.117.310863

Cited by 6 publications

(3 citation statements)

References 8 publications

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“…miRNAs are involved in the regulation of many biological and physiological processes, including organ development and the stabilization of tissue function in response to injury or disease (42). Many of the functional effects produced by exosomes are mediated by exosomal miRNAs that are specific to the exosomes' cells of origin, and although several miRNAs appear to be beneficial for myocardial recovery after MI (43), our knowledge of their potential role in clinical applications is far from complete.…”

Section: Discussionmentioning

confidence: 99%

Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

et al. 2020

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Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium. In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

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Section: Discussionmentioning

confidence: 99%

Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

et al. 2020

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“…Perhaps the time of miR administration is important, but if that is so, there is no clinical applicability for miR administration at the very onset of coronary occlusion in patients, as mentioned above. Another critical question is whether the beneficial effects of miR mimics observed in the two above-mentioned studies in a model of acute MI can be reproduced in more chronic MI models, after LV remodeling and dysfunction have been established [ 47 ]. Further experiments should be considered to address this question.…”

Section: Discussionmentioning

confidence: 99%

Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction

et al. 2021

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Intramyocardial injection of synthetic microRNAs (miRs) has recently been reported to be beneficial after myocardial infarction (MI). We conducted a randomized blinded study to evaluate the efficacy and reproducibility of this strategy in a mouse model of reperfused MI using rigorous methodology. Mice undergoing a 60-min coronary occlusion followed by reperfusion were randomly assigned to control miR, hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p mimic treatment. Intramyocardial injections of miRs were performed in the border zone right after reperfusion. At 8 weeks after MI, there were no significant differences in ejection fraction (EF) among groups (EF = 27.1 ± 0.4% in control group [n = 6] and 25.9 ± 0.5%, 26.0 ± 0.8%, and 26.6 ± 0.6% in hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p groups, respectively [n = 9 each]). Net change (delta) in EF at 8 weeks compared with day 3 after MI was − 4.1% in control and − 3.2%, − 2.4%, and − 0.4% in the miR-treated groups (P = NS). Assessment of cardiac function by hemodynamic studies (a method independent of echocardiography) confirmed that there was no difference in left ventricular systolic or diastolic function among groups. Consistent with the functional data, histological analysis showed no difference in scar size, cardiomyocyte area, capillary density, collagen content, or apoptosis among groups. In conclusion, this randomized, blinded study demonstrates that intramyocardial injection of a single dose of synthetic hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p mimic does not improve cardiac function or remodeling in a murine model of reperfused MI. The strategy of using synthetic miR mimics for cardiac repair after MI needs to be evaluated with rigorous preclinical studies before its potential clinical translation.

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“…Another modification that is being used to improve the uptake of naked nucleic acids by cells is through chemical modification to mRNA to reduce the activation of the immune system and improve the stability of the RNA. These modified mRNAs are attractive agents for short-term gene delivery to the myocardium [99].…”

Section: Non-viral Vectorsmentioning

confidence: 99%

Gene Therapy for Cardiac Transplantation

Mendiola¹,

Chiang²,

Roan³

et al. 2022

Heart Transplantation - New Insights in Therapeutic Strategies

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Gene therapy is an advanced treatment approach that alters the genetic composition of cells to confer therapeutic protein or RNA expression to the target organ. It has been successfully introduced into clinical practice for the treatment of various diseases. Cardiac transplantation stands to benefit from applications of gene therapy to prevent the onset of post-transplantation complications, such as primary graft dysfunction, cardiac allograft vasculopathy, and rejection. Additionally, gene therapy can be used to minimize or potentially eliminate the need for immunosuppression post-transplantation. Several animal models and delivery strategies have been developed over the years with the goal of achieving robust gene expression in the heart. However, a method for doing this has yet to be successfully translated into clinical practice. The recent advances in ex vivo perfusion for organ preservation provide potential ways to overcome several barriers to achieving gene therapy for cardiac transplantation into clinical practice. Optimizing the selection of the gene-carrying vector for gene delivery and selection of the therapeutic gene to be conferred is also crucial for being able to implement gene therapy in cardiac transplantation. Here, we discuss the history and current state of research on gene therapy for cardiac transplantation.

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Synthetic MicroRNAs Stimulate Cardiac Repair

Cited by 6 publications

References 8 publications

Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction

Gene Therapy for Cardiac Transplantation

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