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Heun, Yvonn; Pogoda, Kristin; Anton, Martina; Pircher, Joachim; Pfeifer, Alexander; Woernle, Markus; Ribeiro, Andrea; Kameritsch, Petra; Mykhaylyk, Olga; Plank, Christian; Kroetz, Florian; Pohl, Ulrich; Mannell, Hanna (2017): HIF-1 alpha Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2. In: Molecular therapy, Vol. 25, No. 7: pp. 1616-1627
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Abstract

Hypoxia promotes vascularization by stabilization and activation of the hypoxia inducible factor 1 alpha (HIF-1 alpha), which constitutes a target for angiogenic gene therapy. However, gene therapy is hampered by low gene delivery efficiency and nonspecific side effects. Here, we developed a gene transfer technique based on magnetic targeting of magnetic nanopartidelentivirus (MNP-LV) complexes allowing site -directed gene delivery to individual wounds in the dorsal skin of mice. Using this technique, we were able to control HIF-1 alpha dependent wound healing angiogenesis in vivo via site-specific modulation of the tyrosine phosphatase activity of SHP-2. We thus uncover a novel physiological role of SHP-2 in protecting HIF-1 a from proteasomal degradation via a Src kinase dependent mechanism, resulting in HIF-1 a DNA-binding and transcriptional activity in vitro and in vivo. Excitingly, using targeting of MNP-LV complexes, we achieved simultaneous expression of constitutively active as well as inactive SHP-2 mutant proteins in separate wounds in vivo and hereby specifically and locally controlled HIF-la activity as well as the angiogenic wound healing response in vivo. Therefore, magnetically targeted lentiviral induced modulation of SHP-2 activity may be an attractive approach for controlling patho-physiological conditions relying on hypoxic vessel growth at specific sites.