A model for gene therapy of human hereditary lymphedema

MJ Karkkainen, A Saaristo, L Jussila… - Proceedings of the …, 2001 - National Acad Sciences
MJ Karkkainen, A Saaristo, L Jussila, KA Karila, EC Lawrence, K Pajusola, H Bueler
Proceedings of the National Academy of Sciences, 2001National Acad Sciences
Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring
swelling of the extremities, is associated with heterozygous inactivating missense mutations
of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we
describe a mouse model and a possible treatment for primary lymphedema. Like the human
patients, the lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line,
and swelling of the limbs because of hypoplastic cutaneous, but not visceral, lymphatic …
Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we describe a mouse model and a possible treatment for primary lymphedema. Like the human patients, the lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not visceral, lymphatic vessels. Neuropilin (NRP)-2 bound VEGF-C and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia, suggesting that it may participate in the pathogenesis of lymphedema. By using virus-mediated VEGF-C gene therapy, we were able to generate functional lymphatic vessels in the lymphedema mice. Our results suggest that growth factor gene therapy is applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors.
National Acad Sciences