A Novel Proangiogenic Compound
Angiogenesis, the formation of new blood vessels from a preexisting vascular bed, plays a critical role in tissue growth and repair. Angiogenesis is regulated by a complex collaboration between endothelial and mesenchymal cells and the intricate signaling between multiple angiogenic growth factors.
The Angiopoietins, a cluster of angiogenic growth factors, are ligands to Tek/Tie2, a receptor tyrosine kinase that is highly expressed in endothelial cells. Converging lines of evidence have demonstrated that the interaction of these ligands with Tek/Tie2 promote vascular and lymphatic vessel growth and play a crucial role in chronic inflammation, ischemia and wound healing.
Wound healing involves a well choreographed series of molecular activities that ultimately lead to wound closure. Although surgical approaches to correct and restore collateral blood flow to ischemic tissues have improved, issues such as non-amenable small vessel defects as well as the underlying defects that lead to the dysfunctional vasculature, hinder the healing process. As a result, therapeutic modulation of angiogenesis is the favored approach and many clinical trials have explored the possibility of promoting angiogenesis through the addition of a single growth factor, most often VEGF.
While shown to be highly angiogenic, VEGF goes on to produce vessels that are poorly ordered and highly leaky. However, preclinical studies which included the addition of Angiopoietin 1 (Ang) to the VEGF cocktail have eliminated vascular permeability and restored a more normal pattern of vessel growth. Unfortunately, protein isolation and the inability to retain consistent activity levels of Ang have hindered the therapeutic application of the recombinant compound.
Our invention is an Ang mimetic that could be used on its own or in combination with VEGF to promote angiogenesis and treat numerous abnormalities that directly or indirectly affect the vasculature. The majority of our in vivo efficacy data has been generated using a mouse model of diabetic ulcers.
The main advantages of this technology are:
- Ease of manufacture and reduced cost compared to recombinant
- Consistent activity levels compared to native or recombinant
- Ang has been shown to produce well ordered, non-leaky vasculature
and has also been shown to work in combination with VEGF
- Binding of Ang mimetic is specific to the Tek/Tie 2 receptor which
activates many downstream events required for wound healing
and vascular formation
Two primary forms of pathological angiogenesis exist. They can be crudely characterized by an overgrowth of dysfunctional poorly ordered and leaky vessels as seen in diabetic retinopathy, or a relative absence or reduction in vascular density as seen in ischemic limb disease or following myocardial infarct. Additional applications include; pulmonary arterial hypertension, acute lung disease, regenerative medical applications, inflammatory disease and atherosclerosis.
A US provisional patent application has been filed.
The Innovations Group is interested in partnering in the development of this technology.
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