A SEMA3E mutant resistant to cleavage by furins (UNCL-SEMA3E) inhibits choroidal neovascularization

• Published in: Experimental eye research 2016-12, Vol.153, p.186-194
• Main Authors: Toledano, Shira, Lu, Huayi, Palacio, Agustina, Kigel, Boaz, Kessler, Ofra, Allon, Gilad, Barak, Yoreh, Neufeld, Gera, Schaal, Shlomit
• Format: Article
• Language: English
• Subjects: Age related macular degeneration; Angiogenesis; Animals; Choroidal neovascularization; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - genetics; Choroidal Neovascularization - metabolism; Disease Models, Animal; Glycoproteins - administration & dosage; Glycoproteins - genetics; Humans; Intravitreal Injections; Membrane Proteins - administration & dosage; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Point Mutation; Rats; Rats, Long-Evans; RNA-Binding Proteins - administration & dosage; RNA-Binding Proteins - genetics; Semaphorin
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2016.10.004

Abnormal subretinal choroidal neovascularization (CNV) is a major cause of blindness in exudative age-related macular degeneration (AMD). Current anti-angiogenic treatments by VEGF sequestering agents have been successful, but a significant proportion of patients do not respond well to these treatments, and the response of others diminishes over time, suggesting that additional anti-angiogenic agents that function by separate mechanisms may be of use to such patients. We have previously found that a point mutated form of semaphorin-3E resistant to cleavage by furin like pro-protein convertases (UNCL-Sema3E) displays potent anti-angiogenic properties. We therefore determined if UNCL-Sema3E has potential as an inhibitor of CNV formation. We chose to study UNCL-Sema3E rather than wild type sema3E because unlike full length sema3E, the major p61-Sema3E peptide that is produced by cleavage of sema3E with furin like pro-protein convertases activates signal transduction mediated by the ErbB2 receptor and can promote tumor metastasis in addition to its anti-angiogenic activity. UNCL-Sema3E inhibited efficiently vascular endothelial growth factor-A (VEGF), platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) signaling in human umbilical vein derived endothelial cells (HUVEC) and to a lesser extent hepatocyte growth factor (HGF) signal transduction. CNV that was induced in the eyes of C57 black mice by laser photocoagulation was inhibited by 65% (P