Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema

Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash (R) vector that will be evaluated for phase I/IIa clinical trial. Lymphedema is a disorder of the lymphatic system characterized by massive swelling due to the accumulation of undrained interstitial fluid and fibrotic adipose tissue. Regenerative medicine for lymphedema has to combine molecules to repair both superficial capillaries and deeper collecting vessels.Apelin expression is downregulated in lymphedema tissues from patients. Apelin deficiency increases lymphedema in mice. Apelin restores lymphatic collecting vessel pumping and reduces fibrosis. Transient mRNA delivery of Apelin combined to VEGFC restores function in the entire lymphatic network from capillaries to collecting vessels. Lymphedema is a disorder of the lymphatic system characterized by massive swelling due to the accumulation of undrained interstitial fluid and fibrotic adipose tissue. Regenerative medicine for lymphedema has to combine molecules to repair both superficial capillaries and deeper collecting vessels.