1. Update February 2024 Francine Blei, MD
2. Creff, J., et al. (2024). ``Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary Iymphedema.'' EMBO Mol Med. EPub 01/02/2024. Secondary Iymphedema (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 Iymphatic function in LD. We identified the loss of APLN expression in the Iymphedematous 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 Iymphatic 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 Iymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore Iymphatic 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. This study focuses on the role of Apelin (APLN), a prolymphangiogenic and antifibrotic molecule, as a possible therapy for secondary Iymphedema, via gene therapy. Apelin was found to be downregulated in lymphedematous tissue. APLN knockout mice were lymphedematous, which could be reversed with APLN to reestablish Iymphatic vessel pumping and minimize fibrosis. The combination of APLN-VEGF C was synergistically able to reinstate the Iymphatic capillary function. The studies describe the construction of a transient mRNA delivery system using the LentiFlashÒsystem. Through further experiments,
3. Creff, J., et al. (2024). ``Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary Iymphedema.'' EMBO Mol Med. EPub 01/02/2024.
4. Not just fibrotic: endothelial-derived TGFβ maintains contractile function and lymphatic muscle phenotype during homeostasis
5. Hyaluronic Acid Hydrogels with Phototunable Supramolecular Cross-Linking for Spatially Controlled Lymphatic Tube Formation