Nucleoside-modified VEGFC mRNA induces organ-specific lymphatic growth and reverses experimental lymphedema

• Published in: Nature communications Vol. 12; no. 1; pp. 3460 - 18
• Main Authors: Szőke, Dániel, Kovács, Gábor, Kemecsei, Éva, Bálint, László, Szoták-Ajtay, Kitti, Aradi, Petra, Styevkóné Dinnyés, Andrea, Mui, Barbara L., Tam, Ying K., Madden, Thomas D., Karikó, Katalin, Kataru, Raghu P., Hope, Michael J., Weissman, Drew, Mehrara, Babak J., Pardi, Norbert, Jakus, Zoltán
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 14/1; 14/34; 14/35; 14/63; 38/1; 38/109; 38/35; 38/77; 38/90; 38/91; 45/77; 631/136/290; 631/61/350/354; 631/61/391; 64/110; 64/60; 82/1; 82/29; 82/51; 82/80; Animal models; Animals; Blood Vessels - pathology; Cell Proliferation - drug effects; Degradation; Diphtheria Toxin - pharmacology; Disease Models, Animal; Dosage; Encapsulation; Growth factors; HEK293 Cells; Humanities and Social Sciences; Humans; Immunity - drug effects; Injections, Intradermal; Lipids; Lipids - administration & dosage; Lipids - chemistry; Lymphangiogenesis - genetics; Lymphatic system; Lymphatic Vessels - drug effects; Lymphatic Vessels - pathology; Lymphedema; Lymphedema - pathology; Mice; Mice, Inbred C57BL; mRNA; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nucleosides; Nucleosides - metabolism; Organ Specificity; Organs; Poly C - pharmacology; Quality of life; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Tamoxifen - pharmacology; Vascular endothelial growth factor; Vascular endothelial growth factor C; Vascular Endothelial Growth Factor C - administration & dosage; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23546-6

Lack or dysfunction of the lymphatics leads to secondary lymphedema formation that seriously reduces the function of the affected organs and results in degradation of quality of life. Currently, there is no definitive treatment option for lymphedema. Here, we utilized nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNPs) encoding murine Vascular Endothelial Growth Factor C (VEGFC) to stimulate lymphatic growth and function and reduce experimental lymphedema in mouse models. We demonstrated that administration of a single low-dose of VEGFC mRNA-LNPs induced durable, organ-specific lymphatic growth and formation of a functional lymphatic network. Importantly, VEGFC mRNA-LNP treatment reversed experimental lymphedema by restoring lymphatic function without inducing any obvious adverse events. Collectively, we present a novel application of the nucleoside-modified mRNA-LNP platform, describe a model for identifying the organ-specific physiological and pathophysiological roles of the lymphatics, and propose an efficient and safe treatment option that may serve as a novel therapeutic tool to reduce lymphedema. Dysfunction of the lymphatic system leads to secondary lymphedema and results in degradation of quality of life. Here, the authors show that delivery of nucleoside-modified Vascular Endothelial Growth Factor C (VEGFC) mRNA, encapsulated in lipid nanoparticles, induces organ-specific lymphatic growth and reverses experimental lymphedema.