학술논문
Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine
Document Type
article
Author
Leif Carlsson; Jonathan C. Clarke; Christopher Yen; Francine Gregoire; Tamsin Albery; Martin Billger; Ann-Charlotte Egnell; Li-Ming Gan; Karin Jennbacken; Edvin Johansson; Gunilla Linhardt; Sofia Martinsson; Muhammad Waqas Sadiq; Nevin Witman; Qing-Dong Wang; Chien-Hsi Chen; Yu-Ping Wang; Susan Lin; Barry Ticho; Patrick C.H. Hsieh; Kenneth R. Chien; Regina Fritsche-Danielson
Source
Molecular Therapy: Methods & Clinical Development, Vol 9, Iss , Pp 330-346 (2018)
Subject
Language
English
ISSN
2329-0501
Abstract
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, VEGF-A 165 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 VEGF-A 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. Keywords: modRNA, mRNA, mRNA, VEGF, heart failure