title: Endothelial-targeted Gene Transfer of Hypoxia-inducible Factor-1α Augments Ischemic Neovascularization Following Systemic Administration.
abstract: Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of the response to low oxygen levels and has been used for therapeutic angiogenesis. Various routes of administration have been used for delivering genes to the ischemic region including the intramuscular (IM) and intraarterial routes. When compared with these delivery methods, the intravenous (IV) route confers many advantages, including less invasiveness and lower cost. However, its use is hampered by the fact that it does not result in specific and robust tissue expression of the genes. Our aim was to determine the feasibility, safety, and therapeutic efficacy of systemic administration of adenoviral-mediated HIF-1α targeted to the endothelium. Using confocal microscopy and biodistribution studies we demonstrated that a modified murine preproendothelin-1 promoter (PPE1-3x) can target gene expression specifically to endothelial cells within ischemic muscle following systemic IV administration in C57BL/6 mice. Accordingly, an adenovirus expressing a PPE1-3x-regulated stabilized HIF-1α molecule, further activated by constitutive activation of its C-transactivation domain (C-TAD), was created. Systemic tail-vein administration of this adenovirus in a mouse hindlimb ischemia model resulted in enhanced blood perfusion, improved clinical outcome, and increased capillary density without systemic toxicity, in contrast to the profound systemic side effects and lack of therapeutic efficacy following cytomegalovirus (CMV)-regulated HIF-1α administration. Collectively, these data suggest that transcriptionally controlled systemic proangiogenic gene therapy is feasible, safe, and efficacious.
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Reshef
authors.initials: R
authors.lastname: Tal
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Rofe
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Feige
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Nira
authors.initials: N
authors.lastname: Varda-Bloom
authors.affiliation: Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Afek
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel.
authors.forename: Livnat
authors.initials: L
authors.lastname: Bangio
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Hodish
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Greenberger
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Peled
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
authors.affiliation: Vascular Biogenics Ltd., Or-Yehuda, Israel; The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: dror@vbl.co.il.
authors.forename: Dror
authors.initials: D
authors.lastname: Harats