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 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.
Karkkainen
M J
MJ
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Hospital, Biomedicum Helsinki, University of Helsinki, P.O.B. 63 (Haartmaninkatu 8), 00014 Helsinki, Finland.
Saaristo
A
A
Jussila
L
L
Karila
K A
KA
Lawrence
E C
EC
Pajusola
K
K
Bueler
H
H
Eichmann
A
A
Kauppinen
R
R
Kettunen
M I
MI
Yla-Herttuala
S
S
Finegold
D N
DN
Ferrell
R E
RE
Alitalo
K
K
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008209:Lymphedema / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000032:analysis; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D017978:Receptors, Growth Factor / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
D016228:Endothelial Growth Factors; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3