Gene

Biology

Messenger RNA

Angiogenesis

VEGF receptors

Microdialysis

Therapeutic angiogenesis

Biochemistry

Placebo

Immunology

Alternative medicine

Laser Doppler velocimetry

Central nervous system

Internal medicine

Pharmacology

Medicine

Blood flow

Chemistry

Saline

Vascular endothelial growth factor

Perfusion

Intradermal injection

Pathology

Nature Communications

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.

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