Therapeutic Potential of Anti-Angiogenic Multi-Target N,O-Sulfated E. Coli K5 Polysaccharide in Diabetic Retinopathy

摘要

Vascular endothelial growth factor (VEGF) blockers have been developed for the treatment of proliferative diabetic retinopathy (PDR), the leading cause of visual impairments in the working-age population in the Western world. However, limitations to anti-VEGF therapies may exist because of the local production of others pro-angiogenic factors that may cause resistance to anti-VEGF interventions. Thus, novel therapeutic approaches targeting additional pathways are required. Here, we identified a sulfated derivative of the E. coli polysaccharide K5 [K5-N,OS(H)] as a multi-target molecule highly effective in inhibiting VEGF-driven angiogenic responses in different in vitro, ex vivo and in vivo assays, including a murine model of oxygen-induced retinopathy. Furthermore, K5-N,OS(H) binds a variety of heparin-binding angiogenic factors upregulated in PDR vitreous humor besides VEGF, thus inhibiting their biological activity. Finally, K5-N,OS(H) hampers the angiogenic activity exerted in vitro and in vivo by human vitreous fluid samples collected from PDR patients. Together, the data provide compelling experimental evidence that K5-N,OS(H) represents an anti-angiogenic multi-target molecule with potential implications for the therapy of pathologic neovessel formation in the retina of PDR patients.