title: Endothelial-targeted gene transfer of hypoxia-inducible factor-1alpha augments ischemic neovascularization following systemic administration.
abstract: Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha 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-1alpha 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.
authors.forename: Reshef
authors.initials: R
authors.lastname: Tal
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Karen
authors.initials: K
authors.lastname: Rofe
authors.forename: Erez
authors.initials: E
authors.lastname: Feige
authors.forename: Nira
authors.initials: N
authors.lastname: Varda-Bloom
authors.forename: Arnon
authors.initials: A
authors.lastname: Afek
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Livnat
authors.initials: L
authors.lastname: Bangio
authors.forename: Israel
authors.initials: I
authors.lastname: Hodish
authors.forename: Shoshana
authors.initials: S
authors.lastname: Greenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Peled
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004727:Endothelium / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013379:Substrate Specificity; D019076:Transgenes / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger