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.
Highlights
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
HEK293T cell cultures were transfected with 1 μg of Poly (C) RNA-lipid nanoparticles (LNPs) or Vascular Endothelial Growth Factor C (VEGFC) messenger RNA (mRNA)-LNPs and cell lysates and cell culture supernatants were subjected to Western blot and ELISA analyses 8 hours, 1, 2, 4, 8, and 12 days after the treatment
Nucleoside-modified mRNA-LNP is a novel, highly effective, and safe therapeutic modality that is used for vaccine development, protein replacement therapy, and gene editing in preclinical models and human trials[34,35,36,37,38,40,41]
Summary
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. Adenovirus and AAV-based delivery of human and murine VEGFC has been shown to be effective in mice and domestic pigs to induce lymphatic growth; a drug candidate entered a Phase II clinical trial (NCT03658967)[1,23,24,25,26,27,28,29,30,31] These delivery platforms have major drawbacks such as pre-existing host immunity, anti-vector immune responses, difficulties with regulation and toxicity that may hinder application in clinical practice[32]. Genomic integration of AAV2 has been shown to lead to hepatocellular carcinoma formation that raises serious safety concerns about this delivery approach[33]
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