Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema

Area of Science:

• Biochemistry
• Cell Biology
• Ophthalmology

Background:

• Tie2 receptor tyrosine kinase is crucial for vascular stability, regulated by Angiopoietin-1 (Angpt1) and Angiopoietin-2 (Angpt2).
• Hypoxia increases Angpt2 and vascular endothelial-protein tyrosine phosphatase (VE-PTP), which inhibit Tie2, destabilizing vasculature and promoting leakage.
• VEGF-induced vascular leakage and neovascularization are key pathological features in diabetic retinopathy.

Purpose of the Study:

• To evaluate AKB-9778, a VE-PTP antagonist, as a therapeutic strategy for vascular-related eye diseases.
• To assess the efficacy and safety of Tie2 activation in preclinical models and clinical trials for diabetic macular edema (DME).
• To explore the potential of Tie2 activation as a treatment or preventive measure for diabetic retinopathy.

Main Methods:

• Preclinical studies involving VEGF-induced leakage and ocular neovascularization models.
• Two Phase II clinical trials administering subcutaneous AKB-9778 to DME patients, often in combination with VEGF suppression.
• Analysis of preliminary data from AKB-9778 monotherapy in diabetic retinopathy.

Main Results:

• AKB-9778 reduced VEGF-induced leakage and ocular neovascularization in preclinical models.
• AKB-9778 demonstrated additive benefits when combined with VEGF suppression in preclinical studies.
• In DME clinical trials, AKB-9778 was safe and provided added benefit to VEGF suppression; preliminary data suggest monotherapy improves diabetic retinopathy.

Conclusions:

• Tie2 activation by inhibiting VE-PTP represents a promising therapeutic strategy.
• AKB-9778 is a safe and effective agent for enhancing Tie2 signaling in vascular diseases.
• Targeting Tie2 activation holds potential for treating and preventing diabetic retinopathy and other related conditions.