PRODUCTION AND APPLICATION OF ANGIOSTATINS FOR THE TREATMENT OF OCULAR NEOVASCULAR DISEASES

Abstract

Angiostatins comprise a group of kringle-containing proteolytically-derived plasminogen/plasmin fragments, which act as potent inhibitory mediators of endothelial sells proliferation and migration. Angiostatins are involved in modulation of vessel growth in healthy tissues and various pathological conditions associated with aberrant neovascularization. The aim of the present paper was to summarize available information, including our own experimental data, on prospects of angiostatin application for treatment of ocular neovascular diseases (OND), focusing on retinal pathologies and corneal injury. In particular, literature data on prospective and retrospective studies, clinical trials and animal models relating to the pathophysiology, investigation and management of OND are described. Special emphasis was made on the laboratory approaches of production of different angiostatin isoforms, as well as comparison of antiangiogenic capacities of native and recombinant angiostatin polypeptides. Several studies reported that angiostatins may completely abolish pathologic angiogenesis in diabetic proliferative retinopathy without affecting normal retinal vessel development and without exhibiting adverse side effects. Angiostatins have been tested as a tool for corneal antiangiogenesis target therapy in order to manage diverse ocular surface pathological conditions induced by traumas, chemical burns, previous surgery, chronic contact lens wear, autoimmune diseases, keratitis and viral infections (herpes, COVID-19), corneal graft rejection, etc. Among all known angiostatin species, isolated K5 plasminogen fragment was shown to display the most potent inhibitory activity against proliferation of endothelial cells via triggering multiple signaling pathways, which lead to cell death and resulting angiogenesis suppression. Application of adenoviral genetic construct encoding angiostatin K5 as a promising tool for OND treatment illustrates a vivid example of upcoming revolution in local gene therapy. Further comprehensive studies are necessary to elucidate the clinical potential and optimal regimes of angiostatin-based intervention modalities for treating ocular neovascularization.

Keywords

• angiostatins
• ocular neovascular diseases
• retinopathy
• corneal neovascularization
• antiangiogenic therapy
• local gene delivery.