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

Li-Ming Gan (), Maria Lagerström-Fermér, Leif G. Carlsson, Cecilia Arfvidsson, Ann-Charlotte Egnell, Anna Rudvik, Magnus Kjaer, Anna Collén, James D. Thompson, John Joyal, Ligia Chialda, Thomas Koernicke, Rainard Fuhr, Kenneth R. Chien and Regina Fritsche-Danielson
Additional contact information
Li-Ming Gan: AstraZeneca Gothenburg
Maria Lagerström-Fermér: AstraZeneca Gothenburg
Leif G. Carlsson: AstraZeneca Gothenburg
Cecilia Arfvidsson: AstraZeneca Gothenburg
Ann-Charlotte Egnell: AstraZeneca Gothenburg
Anna Rudvik: AstraZeneca Gothenburg
Magnus Kjaer: AstraZeneca Gothenburg
Anna Collén: AstraZeneca Gothenburg
James D. Thompson: Moderna, Inc., 200 Technology Square
John Joyal: Moderna, Inc., 200 Technology Square
Ligia Chialda: PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31
Thomas Koernicke: PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31
Rainard Fuhr: PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31
Kenneth R. Chien: Karolinska Institutet
Regina Fritsche-Danielson: AstraZeneca Gothenburg

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08852-4

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