PMID- 30787295 OWN - NLM STAT- MEDLINE DCOM- 20190403 LR - 20200309 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 10 IP - 1 DP - 2019 Feb 20 TI - Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. PG - 871 LID - 10.1038/s41467-019-08852-4 [doi] LID - 871 AB - 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. FAU - Gan, Li-Ming AU - Gan LM AUID- ORCID: 0000-0003-2933-1404 AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. li-ming.gan@astrazeneca.com. AD - 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. AD - Department of Cardiology, Sahlgrenska University Hospital, Bla straket 5, 413 45, Gothenburg, Sweden. li-ming.gan@astrazeneca.com. FAU - Lagerstrom-Fermer, Maria AU - Lagerstrom-Fermer M AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Carlsson, Leif G AU - Carlsson LG AD - Cardiovascular, Renal and Metabolism IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Arfvidsson, Cecilia AU - Arfvidsson C AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Egnell, Ann-Charlotte AU - Egnell AC AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Rudvik, Anna AU - Rudvik A AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Kjaer, Magnus AU - Kjaer M AD - Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Collen, Anna AU - Collen A AD - Cardiovascular, Renal and Metabolism IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. FAU - Thompson, James D AU - Thompson JD AD - Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA. FAU - Joyal, John AU - Joyal J AD - Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA. FAU - Chialda, Ligia AU - Chialda L AD - PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31, 14050, Berlin, Germany. FAU - Koernicke, Thomas AU - Koernicke T AD - PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31, 14050, Berlin, Germany. FAU - Fuhr, Rainard AU - Fuhr R AD - PAREXEL Early Phase Clinical Unit, Westend Clinic, House 31, 14050, Berlin, Germany. FAU - Chien, Kenneth R AU - Chien KR AD - Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden. AD - Integrated Cardio Metabolic Center, Karolinska Institutet, Blickagangen 6, SE-141 57, Huddinge, Sweden. FAU - Fritsche-Danielson, Regina AU - Fritsche-Danielson R AD - Cardiovascular, Renal and Metabolism IMED Biotech Unit, AstraZeneca Gothenburg, Pepparedsleden 1, 431 50, Molndal, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190220 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Placebos) RN - 0 (RNA, Messenger) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) SB - IM MH - Adult MH - Aged MH - Diabetes Mellitus, Type 2/*therapy MH - Genetic Therapy MH - Humans MH - Injections, Intradermal MH - Male MH - Middle Aged MH - Neovascularization, Physiologic/*physiology MH - Placebos/administration & dosage MH - RNA, Messenger/*adverse effects/genetics/*therapeutic use MH - Regional Blood Flow/genetics MH - Skin/*blood supply MH - Vascular Endothelial Growth Factor A/*genetics PMC - PMC6382754 COIS- This study was funded by AstraZeneca. AstraZeneca develops and markets treatments for cardiovascular and metabolic disorders. AZD8601 (VEGF-A-modified mRNA) is an investigational medicinal product with no approved indication. L.-M.G., M.L.-F., L.G.C., C.A., A.-C.E., A.R., M.K., A.C. and R.F.-D. are employees of AstraZeneca and may own stock or stock options. J.D.T. and J.J. are employees of Moderna, Inc., and may own stock or stock options. L.C., T.K., and R.F. are current or former employees of PAREXEL. AstraZeneca provided funding to PAREXEL for conducting this study. K.R.C. is an advisor and chair of the External Science Panel for AstraZeneca and a member of the Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Center in Huddinge, and receives support for these services, as well as research support through the Karolinska Institutet Center. He is also a co-founder and equity holder of Moderna, Inc. EDAT- 2019/02/23 06:00 MHDA- 2019/04/04 06:00 PMCR- 2019/02/20 CRDT- 2019/02/22 06:00 PHST- 2018/10/23 00:00 [received] PHST- 2019/02/04 00:00 [accepted] PHST- 2019/02/22 06:00 [entrez] PHST- 2019/02/23 06:00 [pubmed] PHST- 2019/04/04 06:00 [medline] PHST- 2019/02/20 00:00 [pmc-release] AID - 10.1038/s41467-019-08852-4 [pii] AID - 8852 [pii] AID - 10.1038/s41467-019-08852-4 [doi] PST - epublish SO - Nat Commun. 2019 Feb 20;10(1):871. doi: 10.1038/s41467-019-08852-4.