Lymphangiogenic gene therapy with minimal blood vascular side effects.
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.[1]References
- Lymphangiogenic gene therapy with minimal blood vascular side effects. Saaristo, A., Veikkola, T., Tammela, T., Enholm, B., Karkkainen, M.J., Pajusola, K., Bueler, H., Ylä-Herttuala, S., Alitalo, K. J. Exp. Med. (2002) [Pubmed]
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