Araújo Rute S, Bitoque Diogo B, Silva Gabriela A
CEDOC-Chronic Diseases Research Center, NOVA Medical School, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal.
Bioengineering-Cell Therapies and Regenerative Medicine PhD Program, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal.
Mol Ther Nucleic Acids. 2020 Sep 2;22:329-339. doi: 10.1016/j.omtn.2020.08.036. eCollection 2020 Dec 4.
Intravitreal injections of anti-vascular endothelial growth factor drugs have become the gold standard treatment for diabetic retinopathy (DR). However, several patients are classified as non-responders or poor responders to treatment. Therefore, it is essential to study alternative target molecules. We have previously shown that the progression of DR in the Ins2 mouse reflects the imbalance between pro- and anti-angiogenic molecules found in the human retina. We report, for the first time, the therapeutic potential of a dual-acting antiangiogenic non-viral gene therapy. We have used an expressing vector encoding both the pigment epithelium-derived factor gene and a short hairpin RNA (shRNA) targeted to the placental growth factor to restore the balance between these factors in the retina. Twenty-one days after a single subretinal injection, we observed a marked decrease in the inflammatory response in the neural retina and in the retinal pigment epithelium, together with reduced vascular retinal permeability in the treated diabetic mouse. These results were accompanied by the restoration of the retinal capillary network and regression of neovascularization, with significant improvement of DR hallmarks. Concomitant with the favorable therapeutic effects, this approach did not affect retinal ganglion cells. Hence our results provide evidence toward the use of this approach in DR treatment.
玻璃体内注射抗血管内皮生长因子药物已成为糖尿病视网膜病变（DR）的金标准治疗方法。然而，有几位患者被归类为治疗无反应者或反应不佳者。因此，研究替代靶分子至关重要。我们之前已经表明，Ins2小鼠中DR的进展反映了人类视网膜中促血管生成分子和抗血管生成分子之间的失衡。我们首次报告了一种双作用抗血管生成非病毒基因疗法的治疗潜力。我们使用了一种表达载体，该载体编码色素上皮衍生因子基因和靶向胎盘生长因子的短发夹RNA（shRNA），以恢复视网膜中这些因子之间的平衡。在单次视网膜下注射21天后，我们观察到治疗的糖尿病小鼠神经视网膜和视网膜色素上皮中的炎症反应明显降低，同时视网膜血管通透性降低。这些结果伴随着视网膜毛细血管网络的恢复和新生血管的消退，DR特征得到显著改善。伴随着良好的治疗效果，这种方法并未影响视网膜神经节细胞。因此，我们的结果为在DR治疗中使用这种方法提供了证据。
