10/12 臨床研セミナーのご案内 1
日時 ：平成１７年１０月１２日（水曜日） １４：００?１５：３０
会場 ：（財）東京都医学研究機構 東京都臨床医学総合研究所 ２階会議室
演題 ：Induction of functional neovascularization by gene therapy using AAV vectors
演者：Mauro Giacca（Director&s_comma; International Centre for Genetic Engineering and Biotechnology [ICGEB]&s_comma; Trieste&s_comma; Italy)
The potential to induce therapeutic angiogenesis and myocardial cell regeneration through gene transfer has engendered much excitement for the possible treatment of ischemic tissues. However&s_comma; a number of crucial issues have still to be solved before successful clinical application&s_comma; including the understanding of whether functional blood vessels can arise as a result of the delivery of a single angiogenic factor&s_comma; or of which are the most suitable vectors for efficient&s_comma; stable and controllable gene delivery to the heart. In this respect&s_comma; the peculiar tropism of vectors based on the adeno-associated virus (AAV) for skeletal and cardiac muscle&s_comma; together with their ability to sustain long term expression are very appealing characteristics for cardiovascular gene therapy. We have recently observed that the delivery of an AAV vector expressing the 165 aa isoform of VEGF (VEGF165) into the skeletal muscle and heart of rodents induces an impressive formation of new capillaries and arteriolae with a 20-120 µm diameter. However&s_comma; these vessels were leaky&s_comma; poorly organized and did not account for the better perfusion of the muscle&s_comma; as indicated by permeability tests and in vivo PET imaging. Strikingly&s_comma; the functional competence of these vessels could be significantly improved by the simultaneous delivery of AAV-Angiopoietin1&s_comma; a factor that is involved in vessel maturation. In the course of these experiments&s_comma; we also noticed that the foci of VEGF neovascularization were always massively infiltrated with CD45+&s_comma; CD11b+ mononuclear cells. These cells were found to derive from the bone marrow (as detected by bone marrow transplantation and FISH analysis) and to be recruited to the sites of new blood vessel formation through the interaction of VEGF165 with the neuropilin-1 (NP-1) co-receptor&s_comma; as shown by specific siRNA knock down of the NP-1 mRNA. The presence of these mononuclear cells was found to strictly correlate with arteriogenesis: in the case of the delivery of another VEGF isoform (VEGF121)&s_comma; which does not bind NP-1&s_comma; neither cellular infiltrates nor arterial vessels were evident. Thus&s_comma; the recruitment of bone marrow mononuclear cells is essential for arterial formation; in no case&s_comma; however&s_comma; these cells were ever found incorporated in the newly formed vasculature&s_comma; thus ruling out that VEGF165 might trigger a vasculogenesis process sustained by bone marrow-derived progenitors.
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