In diabetic eye disease VE-PTP and Ang-2, factors that decrease Tie2 activity, are upregulated. This results in a significant decrease in Tie2 activation.
Blocking Ang-2 activity, ostensibly to increase Ang-1’s opportunity to activate Tie2, may help to maintain vascular stability.
Our hypothesis, based on our pre-clinical experiments, suggests that removal of Ang-2 may not be the optimal approach to activate the Tie2 receptor. In the complete absence of Ang-2, our scientific results have shown that Tie2 is still deactivated downstream of the angiopoietins by VE-PTP, resulting in an Ang-1-resistant state.
In this state, Ang-1 is not able to maintain Tie2 activity, resulting in a potential loss of blood vessel integrity, which ultimately leads to vascular inflammation, leakage and pathologic neovascularization.
We believe directly blocking VE-PTP could overcome this Ang-1 resistance and activate the Tie2 receptor. Our pre-clinical experiments suggest this may happen regardless of Ang-1 or Ang-2 levels and may ultimately prove to be the most clinically superior way to manipulate activity of the Tie2 receptor.