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Nat Commun. 2019 Feb 20;10(1):871. doi: 10.1038/s41467-019-08852-4.

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

Author information

1
Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Mölndal, Sweden. li-ming.gan@astrazeneca.com.
2
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Arvid Wallgrens backe 1, 413 46, Gothenburg, Sweden. li-ming.gan@astrazeneca.com.
3
Department of Cardiology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden. li-ming.gan@astrazeneca.com.
4
Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Mölndal, Sweden.
5
Cardiovascular, Renal and Metabolism IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Mölndal, Sweden.
6
Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA.
7
PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31, 14050, Berlin, Germany.
8
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden.
9
Integrated Cardio Metabolic Center, Karolinska Institutet, Blickagången 6, SE-141 57, Huddinge, Sweden.

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.

PMID:
30787295
PMCID:
PMC6382754
DOI:
10.1038/s41467-019-08852-4
[Indexed for MEDLINE]
Free PMC Article

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