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

Nat Commun. 2019 Feb 20;10(1):871. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Diabetes Mellitus, Type 2 / therapy*
  • Genetic Therapy
  • Humans
  • Injections, Intradermal
  • Male
  • Middle Aged
  • Neovascularization, Physiologic / physiology*
  • Placebos / administration & dosage
  • RNA, Messenger / adverse effects*
  • RNA, Messenger / genetics
  • RNA, Messenger / therapeutic use*
  • Regional Blood Flow / genetics
  • Skin / blood supply*
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Placebos
  • RNA, Messenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A