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

Dániel Szőke, Gábor Kovács, Éva Kemecsei, László Bálint, Kitti Szoták-Ajtay, Petra Aradi, Andrea Styevkóné Dinnyés, Barbara L. Mui, Ying K. Tam, Thomas D. Madden, Katalin Karikó, Raghu P. Kataru, Michael J. Hope, Drew Weissman, Babak J. Mehrara, Norbert Pardi () and Zoltán Jakus ()
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Dániel Szőke: Semmelweis University School of Medicine
Gábor Kovács: Semmelweis University School of Medicine
Éva Kemecsei: Semmelweis University School of Medicine
László Bálint: Semmelweis University School of Medicine
Kitti Szoták-Ajtay: Semmelweis University School of Medicine
Petra Aradi: Semmelweis University School of Medicine
Andrea Styevkóné Dinnyés: Semmelweis University School of Medicine
Barbara L. Mui: Acuitas Therapeutics
Ying K. Tam: Acuitas Therapeutics
Thomas D. Madden: Acuitas Therapeutics
Katalin Karikó: BioNTech RNA Pharmaceuticals
Raghu P. Kataru: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center
Michael J. Hope: Acuitas Therapeutics
Drew Weissman: University of Pennsylvania, Perelman School of Medicine
Babak J. Mehrara: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center
Norbert Pardi: University of Pennsylvania, Perelman School of Medicine
Zoltán Jakus: Semmelweis University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23546-6

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