Lymphangiogenic gene therapy with minimal blood vascular side effects

A Saaristo, T Veikkola, T Tammela, B Enholm… - The Journal of …, 2002 - rupress.org
A Saaristo, T Veikkola, T Tammela, B Enholm, MJ Karkkainen, K Pajusola, H Bueler
The Journal of experimental medicine, 2002rupress.org
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 …
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.
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