Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissu...

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Published inMolecular therapy. Methods & clinical development Vol. 9; pp. 330 - 346
Main Authors Carlsson, Leif, Clarke, Jonathan C, Yen, Christopher, Gregoire, Francine, Albery, Tamsin, Billger, Martin, Egnell, Ann-Charlotte, Gan, Li-Ming, Jennbacken, Karin, Johansson, Edvin, Linhardt, Gunilla, Martinsson, Sofia, Sadiq, Muhammad Waqas, Witman, Nevin, Wang, Qing-Dong, Chen, Chien-Hsi, Wang, Yu-Ping, Lin, Susan, Ticho, Barry, Hsieh, Patrick C H, Chien, Kenneth R, Fritsche-Danielson, Regina
Format Journal Article
LanguageEnglish
Published United States Elsevier Limited 15.06.2018
American Society of Gene & Cell Therapy
Elsevier
Subjects
Cardiac function
Cardiac muscle
Cell adhesion & migration
Citric acid
Efficiency
Experiments
Fibrosis
Gene expression
Genomes
Heart attacks
Immune response
Immune system
Ischemia
Laboratory animals
Lipids
Medicin och hälsovetenskap
mRNA
Musculoskeletal system
Myocardial infarction
Occlusion
Protein expression
Proteins
Vascular endothelial growth factor
Ventricle
modRNA
heart failure
mRNA
VEGF
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Summary:mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, mRNA improves systolic ventricular function and limits myocardial damage. Following a single administration a week post-infarction in mini pigs, left ventricular ejection fraction, inotropy, and ventricular compliance improved, border zone arteriolar and capillary density increased, and myocardial fibrosis decreased at 2 months post-treatment. Purified mRNA establishes the feasibility of improving cardiac function in the sub-acute therapeutic window and may represent a new class of therapies for ischemic injury.
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These authors contributed equally to this work.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2018.04.003