A model for gene therapy of human hereditary lymphedema

Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous i nactivating missense mutations of the gene encoding vascular endothelial gr owth factor C/D receptor (VEGFR-3). Here, we describe a mouse model and a p ossible treatment for primary lymphedema. Like the human patients, the lymp hedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not viscera l, lymphatic vessels. Neuropilin (NRP)-2 bound VEGF-C and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia, suggesting th at it may participate in the pathogenesis of lymphedema. By using virus-med iated VEGF-C gene therapy, we were able to generate functional lymphatic ve ssels in the lymphedema mice. Our results suggest that growth factor gene t herapy is applicable to human lymphedema and provide a paradigm for other d iseases associated with mutant receptors.