Lymphedema is a disabling condition induced by the accumulation of fluid and fat in the arm or in the leg. It is an untreatable disease that affects 4 millions people in Europe and more than 120 millions people worldwide. It is handicapping, painful and impacts substantially the quality of life. In western countries, lymphedema is generally a consequence of cancer treatments i.e. ten to fifteen percent of women will develop lymphedema after breast cancer. The main objective of Theralymph will be to establish a non-integrative gene therapy for this unmet medical need. The theralymph translational research program brings together bench scientists from 5 European countries and physicians from the hosted Rangueil hospital in which the PI institute is located to perform a Phase I/II trial focusing on women who developed lymphedema after breast cancer. Based on decades of disappointing results of monotherapy-gene delivery in cardiovascular diseases, our approach will be based on multiple gene therapy targeting both superficial lymphatic endothelium and deeper lymphatic collectors. We will identify molecules that possess a synergistic effect with the established lymphangiogenic factor VEGFC. Theralymph project will determine risk factors for lymphedema and cartography the lymphatic network in the pathology. It will decipher whether lymphatic intrinsic molecules or microenvironmental peptides or lipids are modified in the lymphedematous arm to promote the lymphatic dysfunction. Theralymph will validate the best molecule combination that restores the lymphatic drainage in in preclinical lymphedema models before human study. The Phase I/II gene therapy clinical trial will be performed in the vascular medicine department of Toulouse’s hospital, where the PI laboratory is located. This trial will use an innovative technology based on recently developed non-integrative lentiflash lentiviral vectors that allow a transient and highly efficient in vivo gene delivery.