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 inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we describe a mouse model an...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom reprint requests should be addressed at: Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 3, SF-00290 Helsinki, Finland. E-mail: kari.alitalo@helsinki.fI. Communicated by Erkki Ruoslahti, The Burnham Institute, La Jolla, CA
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.221449198