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

• Published in: Nature communications Vol. 10; no. 1; pp. 871 - 9
• Main Authors: Gan, Li-Ming, Lagerström-Fermér, Maria, Carlsson, Leif G., Arfvidsson, Cecilia, Egnell, Ann-Charlotte, Rudvik, Anna, Kjaer, Magnus, Collén, Anna, Thompson, James D., Joyal, John, Chialda, Ligia, Koernicke, Thomas, Fuhr, Rainard, Chien, Kenneth R., Fritsche-Danielson, Regina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 42/109; 42/44; 59; 631/443/319/1642/137/138; 631/443/592/16; 631/61/391; Adult; Aged; Angiogenesis; Biocompatibility; Blood flow; Cardiology and Cardiovascular Disease; cardiovascular gene-therapy; Clinical trials; Coding; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - therapy; Doppler effect; endothelial growth-factor; foot; Forearm; Gene expression; Genetic Therapy; Growth factors; Humanities and Social Sciences; Humans; infarction; injection; Injections, Intradermal; Kardiologi och kardiovaskulära sjukdomar; Male; Microdialysis; Middle Aged; mRNA; multidisciplinary; Neovascularization, Physiologic - physiology; Organic chemistry; Placebos - administration & dosage; Protein expression; Proteins; Regional Blood Flow - genetics; RNA, Messenger - adverse effects; RNA, Messenger - genetics; RNA, Messenger - therapeutic use; Science; Science & Technology - Other Topics; Science (multidisciplinary); Skin; Skin - blood supply; vaccines; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08852-4

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. Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.