A Model for Gene Therapy of Human Hereditary Lymphedema

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 22; pp. 12677 - 12682
• Main Authors: Karkkainen, Marika J., Saaristo, Anne, Jussila, Lotta, Karila, Kaisa A., Lawrence, Elizabeth C., Pajusola, Katri, Bueler, Hansruedi, Eichmann, Anne, Kauppinen, Risto, Kettunen, Mikko I., Ylä-Herttuala, Seppo, Finegold, David N., Ferrell, Robert E., Alitalo, Kari
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-10-2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Adenoviridae - genetics; Amino Acid Sequence; Animals; Antibodies; Biological Sciences; Blood vessels; Dependovirus - genetics; Disease Models, Animal; Endothelial Growth Factors - genetics; Endothelial Growth Factors - metabolism; Gene therapy; Genetic mutation; Genetic Therapy; Humans; Ligands; Lymphatic system; Lymphatic vessels; Lymphedema; Lymphedema - therapy; Male; Medical research; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Milroy's disease; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - analysis; neuropilin 2; Neuropilin-1; Receptor Protein-Tyrosine Kinases - physiology; Receptors; Receptors, Growth Factor - physiology; Skin; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; VEGFR-3 gene
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.221449198

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.