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

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.

Non-liver mRNA Delivery

“…After intraperitoneal injection, increased lymphatic growth was detected in the diaphragm; after intratracheal injection, in the lungs; and after intramuscular administration, in the musculus gastrocnemius. 61 A second line of evidence also suggests that the mRNA drug kinetics change with the route of administration. In mice, intramuscular delivery increased the half-life of mRNA translation nearly 3-fold, from 6.8 h after systemic administration to 20.6 h after intramuscular administration.…”

Pharmacological Treatment of Secondary Lymphedema

“…(Brown et al, 2020) Szoke et al recently reported on the use of nucleoside modified VEGF-C mRNA delivered using lipid nanoparticles to promote organ-specific lymphangiogenesis and treat experimentally induced lymphedema. (Szőke et al, 2021) They showed that injection of the VEGF lipid nanoparticles increased VEGF-C expression locally for as long as 20 days after treatment. This increased VEGF-C production significantly increased lymphangiogenesis that persisted even 60 days after injection.…”

The Impact of mRNA Technology in Regenerative Therapy: Lessons for Oral Tissue Regeneration

“…A single low-dose administration of VEGF-C mRNA-LNPs induced organ-specific lymphatic growth in mice. Most important, treatment with VEGF-C mRNA-LNPs was able to reverse lymphedema and restore lymphatic function in an experimental lymphedema mouse model (Szőke et al 2021).…”