Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single angiogenic mediator, vascular endothelial growth factor (VEGF). Here, we report that aqueous fluid levels of a second vasoactive mediator, angiopoietin-like 4 (ANGPTL4), can help predict the response of patients with nvAMD to anti-VEGF therapies. ANGPTL4 expression was higher in patients who required monthly treatment with anti-VEGF therapies compared with patients who could be effectively treated with less-frequent injections. We further demonstrate that ANGPTL4 acts synergistically with VEGF to promote the growth and leakage of choroidal neovascular (CNV) lesions in mice. Targeting ANGPTL4 expression was as effective as targeting VEGF expression for treating CNV in mice, while simultaneously targeting both was more effective than targeting either factor alone. To help translate these findings to patients, we used a soluble receptor that binds to both VEGF and ANGPTL4 and effectively inhibited the development of CNV lesions in mice. Our findings provide an assay that can help predict the response of patients with nvAMD to anti-VEGF monotherapy and suggest that therapies targeting both ANGPTL4 and VEGF will be a more effective approach for the treatment of this blinding disease.
Yu Qin, Aumreetam Dinabandhu, Xuan Cao, Jaron Castillo Sanchez, Kathleen Jee, Murilo Rodrigues, Chuanyu Guo, Jing Zhang, Jordan Vancel, Deepak Menon, Noore-Sabah Khan, Tao Ma, Stephany Y. Tzeng, Yassine Daoud, Jordan J. Green, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
In vivo nanoparticle-mediated siRNA targeting ANGPTL4 and VEGF is more effective than targeting either angiogenic factor alone for the treatment of laser CNV mice.