Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes

Li-Ming Gan,John Joyal,Cecilia Arfvidsson,Anna Collén,Ann-Charlotte Egnell,Kenneth R Chien,Regina Fritsche-Danielson,Anna Rudvik,Leif G Carlsson,Maria Lagerström-Fermér,Ligia Chialda,Thomas Koernicke,James D Thompson,Rainard Fuhr,Magnus Kjaer

doi:10.1038/s41467-019-08852-4

Abstract

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4–24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.

Highlights

Modified mRNA is an efficient, biocompatible modality for therapeutic protein expression
Pre-specified exploratory objectives were: (1) to evaluate local vascular endothelial growth factor A (VEGF-A) protein production using microdialysis for 28 h after administration; (2) to compare systemic vascular endothelial growth factor (VEGF)-A protein levels after administration with baseline levels; (3) to evaluate the pharmacodynamic effects of VEGF-A mRNA on skin blood flow using laser Doppler fluximetry 4 h after administration; and (4) to evaluate the effects of VEGF-A mRNA on skin blood flow using laser Doppler imaging 7 and 14 days after administration
Exploratory outcomes of the study suggested that VEGF-A encoded and delivered by chemically modified mRNA was produced in the skin and enhanced skin blood flow in men with type 2 diabetes mellitus (T2DM)

Summary

Introduction

Modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. Intradermal VEGFA mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. Rat, and pig models of myocardial infarction, intramyocardial injection of modified mRNA encoding VEGF-A165 (VEGF-A mRNA) led to elevated cardiac VEGFA protein levels and improved heart function and survival, which were associated with improved formation of new blood vessels around the infarct[7,10]. Enhanced differentiation of epicardial progenitor cells toward the endothelial lineage was observed when VEGF-A was delivered with mRNA but not when delivered with a DNA plasmid vector[7] This suggests that the transient and pulse-like expression of VEGF-A from modified mRNA7 was essential for increased activation of quiescent progenitor cells following myocardial injury, with resulting formation of functional new blood vessels[7,10]. A non-translatable variant of VEGF-A mRNA lacked vasodilatory and angiogenic activity in mice[17,18]

Methods

Results

Conclusion