The Journal of Experimental Medicine
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Published 16 September 2002. doi:10.1084/jem.20020587
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© Rockefeller University Press, 0022-1007/2002/9/719/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 6, September 16, 2002 719-730

Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects

Anne Saaristo1, Tanja Veikkola1, Tuomas Tammela1, Berndt Enholm1, Marika J. Karkkainen1, Katri Pajusola2, Hansruedi Bueler2, Seppo Ylä-Herttuala3 and Kari Alitalo1

1 Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, the Haartman Institute and Helsinki University Central Hospital, University of Helsinki, 00014 Helsinki, Finland
2 Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland
3 A.I. Virtanen Institute and Department of Medicine, University of Kuopio, 70211 Kuopio, Finland

Address correspondence to Dr. Kari Alitalo, Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, P.O.B. 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland. Phone: 358-9-1912 5511; Fax: 358-9-1912 5510; E-mail: Kari.Alitalo{at}helsinki.fi

Recent work from many laboratories has demonstrated that the vascular endothelial growth factor-C/VEGF-D/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and that mutations of the Vegfr3 gene are associated with hereditary lymphedema. Furthermore, VEGF-C gene transfer to the skin of mice with lymphedema induced a regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. To avoid these blood vascular side effects of VEGF-C, we constructed a viral vector for a VEGFR-3–specific mutant form of VEGF-C (VEGF-C156S) for lymphedema gene therapy. We demonstrate that VEGF-C156S potently induces lymphangiogenesis in transgenic mouse embryos, and when applied via viral gene transfer, in normal and lymphedema mice. Importantly, adenoviral VEGF-C156S lacked the blood vascular side effects of VEGF and VEGF-C adenoviruses. In particular, in the lymphedema mice functional cutaneous lymphatic vessels of normal caliber and morphology were detected after long-term expression of VEGF-C156S via an adeno associated virus. These results have important implications for the development of gene therapy for human lymphedema.

Key Words: lymphedema • lymphatic endothelium • VEGF-C • VEGFR-2 • VEGFR-3


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