PhD Scientific Days 2021

Budapest, 7-8 July 2021

MO_II_P: Molecular Sciences II. Posters

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

Dániel Szőke1,2, Gábor Kovács1,2, Éva Kemecsei1,2, László Bálint1,2, Kitti Szoták-Ajtay1,2, Petra Aradi1,2, Andrea Styevkóné Dinnyés1,2, Barbara L. Mui3, Ying K. Tam3, Thomas D. Madden3, Katalin Karikó4, Raghu P. Kataru5, Michael J. Hope3, Drew Weissman6, Babak J. Mehrara5, Norbert Pardi6 & Zoltán Jakus1,2
1 Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
2 MTA-SE „Lendület” Lymphatic Physiology Research Group of
the Hungarian Academy of Sciences and the Semmelweis University, Budapest, Hungary.
3 Acuitas Therapeutics, Vancouver, BC, Canada.
4 BioNTech RNA
Pharmaceuticals, Mainz, Germany.
5 Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New
York, NY, USA.
6 University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

Text of the 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.
This work was supported by the Lendület program of the Hungarian Academy of Sciences (LP2014-4/2019 to Z. Jakus), the National Research, Development and Innovation Office (NVKP_16-2016-1-0039 to Z. Jakus), the European Union and the Hungarian Government (VEKOP-2.3.2-16-2016-00002 to Z. Jakus and EFOP-3.6.3-VEKOP-16-2017-00009 to D. Szőke and G. Kovács), and the Higher Education Institutional Excellence Program of the Ministry for Innovation and Technology in Hungary, within the framework of the Molecular Biology thematic program of the Semmelweis University. D. Weissman and N. Pardi were supported by the NIAID of the NIH under award numbers R01-AI050484, R01-AI124429, R01-AI084860, and R01-AI146101.
Published in Nature Communications on 08 June 2021
https://doi.org/10.1038/s41467-021-23546-6

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine