Moshe Y' Flugelman

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Therapeutic Angiogenesis Where are the new
vessels leading us?

• Moshe Y. Flugelman
• Department of Cardiovascular Medicine
• Lady Davis Carmel Medical Center
• Haifa, Israel

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Presentation outline

• What is Angiogenesis?
• Protein, gene and cell therapies to achieve
  therapeutic angiogenesis - Review of angiogenesis
  studies
• Integrated approach for arteriogenesis

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What is angiogenesis?

• Three different processes
• - Vasculogenesis (embryo)
• - Capillary sprouting
• - Arteriogenesis

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Key genes in angiogenesis
Hanahan, Science 1997
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Capillary sprouting

• Mostly endothelial cell proliferation
• Increased number of capillaries can only lead to
  a limited flow increase

Capillaries in hind limb muscle
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Arteriogenesis

• Remodeling of pre-existing vessels
• Involves multiple cells and cytokines
• Can restore flow to near normal levels

Angiogenesis Collaterals
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Induction of angiogenesis

• Angiogenic factor
• - Proteins VEGF, FGF
• - Genes and transcription factors VEGF,
  Del-1, FGF4 (plasmid, viral vectors)
• - Cells Bone marrow, circulating
  progenitors
• Mode of delivery
• - Intramuscular, intra-arterial

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Angiogenesis Studies Phase II and III
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Summary clinical studies

• The therapeutic goal should be arteriogenesis
• Single factor intervention may be insufficient
  for induction of therapeutic angiogenesis

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Integrated approach

• Use of more than one cell type
• The cells are activated by angiogenic genes
• The cell are injected intra-arterial at site of
  collatterals

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Summary Integrated approach

• Increased blood flow through the collaterals was
  detected after autologous somatic cell
  transplantation
• MultiGene and MultiCell approach resulted in
  Arteriogenesis

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Arteriogenesis

• Angiogenic factors and cytokines
• Relevant cells Successful
  therapeutic angiogenesis
• Flow mediated shear stress