Karen A Vincent And Ralph A Kelly

Abstract: Repair and regeneration of the vasculature in patients with advanced ischemic disease, or therapeutic neovascularization, can be achieved through the enhancement of both angiogenesis - the de novo development of capillaries and arteriogenesis - the remodeling of pre-existing arterioles into larger vessels. The regulation of both of these processes is extremely complex and as a result, only modest success has been achieved in most clinical trials using single angiogenic growth factors whether administered as recombinant proteins or as therapeutic transgenes. Alternative strategies include the co-delivery of two or more angiogenic cytokines or the induction of multiple pro-angiogenic signaling cascades through the administration of a single gene. One such candidate is Hypoxia-Inducible Factor-1 (HIF-1), a heterodimeric transcription factor composed of HIF-1a and HIF-1|3 subunits. Activity of HIF-1 is regulated by oxygen concentration through regulation of protein stability and transcriptional activity of the HIF-1 a subunit. Because HIF-1 regulates the expression of a variety of genes involved in angiogenesis, therapeutic strategies targeting this factor hold promise for the generation and growth of morphologically and physiologically normal vessels. In this review, we provide information on the scientific rationale, enabling experimental animal data, and early clinical trial experience of a constitutively active form of HIF-1 a

Keywords: HIF-1; angiogenesis, therapeutic neovascularization, gene therapy, VEGF, prolyl hydroxylases, ischemia

Abbreviations: HIF, Hypoxia-inducible factor EPC, endothelial progenitor cell; VEGF, vascular endothelial growth factor; Ang, angiopoietin; platelet derived growth factor PDGF; FGF fibroblast growth factor; PlGF, placental growth factor; HGF, hepatocyte growth factor; MCP-1, monocyte chemotactic protein-1; GM-CSF, granulocyte-monocyte colony-stimulating factor; IGF, insulin-like growth factor; TGF|3, transforming growth factor —3; ARNT, aryl hydrocarbon receptor nuclear translocator; PAS, Per-Arnt-Sim; EPAS-1, endothelial PAS protein-1; bHLH: basic helix-loop-helix; TAD, transcriptional activation domain; CBP, CREB binding protein, SRC-1, steroid receptor co-activator; TIF-2, transcriptional intermediary factor-2; HDAC, HIF-1 a-interacting histone deacetylase;

Correspondence to: Ralph A. Kelly MD, Vice President, Clinical Affairs, Genzyme Corporation, 15 Pleasant St. Connector, P.O. Box 9322, Framingham, MA 01701-9322, Phone: 617-761-8715, FAX: 508-271-2692, E-mail: [email protected]

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