Bigot Karine, Gondouin Pauline, Bénard Romain, Montagne Pierrick, Youale Jenny, Piazza Marie, Picard Emilie, Bordet Thierry, Behar-Cohen Francine
Eyevensys, Biopark, 11 rue Watt, 75013 Paris, France.
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, 75006 Paris, France.
Pharmaceutics. 2020 Sep 1;12(9):836. doi: 10.3390/pharmaceutics12090836.
Dysregulation of iron metabolism is observed in animal models of retinitis pigmentosa (RP) and in patients with age-related macular degeneration (AMD), possibly contributing to oxidative damage of the retina. Transferrin (TF), an endogenous iron chelator, was proposed as a therapeutic candidate. Here, the efficacy of TF non-viral gene therapy based on the electrotransfection of pEYS611, a plasmid encoding human TF, into the ciliary muscle was evaluated in several rat models of retinal degeneration. pEYS611 administration allowed for the sustained intraocular production of TF for at least 3 and 6 months in rats and rabbits, respectively. In the photo-oxidative damage model, pEYS611 protected both retinal structure and function more efficiently than carnosic acid, a natural antioxidant, reduced microglial infiltration in the outer retina and preserved the integrity of the outer retinal barrier. pEYS611 also protected photoreceptors from N-methyl-N-nitrosourea-induced apoptosis. Finally, pEYS611 delayed structural and functional degeneration in the RCS rat model of RP while malondialdehyde (MDA) ocular content, a biomarker of oxidative stress, was decreased. The neuroprotective benefits of TF non-viral gene delivery in retinal degenerative disease models further validates iron overload as a therapeutic target and supports the continued development of pEY611 for treatment of RP and dry AMD.
在视网膜色素变性（RP）动物模型和年龄相关性黄斑变性（AMD）患者中观察到铁代谢失调，这可能导致视网膜的氧化损伤。转铁蛋白（TF）是一种内源性铁螯合剂，被提议作为一种治疗候选物。在此，基于将编码人TF的质粒pEYS611电转染到睫状肌中，对TF非病毒基因疗法在几种视网膜变性大鼠模型中的疗效进行了评估。分别在大鼠和兔子中，给予pEYS611可使眼内持续产生TF至少3个月和6个月。在光氧化损伤模型中，pEYS611比天然抗氧化剂鼠尾草酸更有效地保护视网膜结构和功能，减少外视网膜中的小胶质细胞浸润并保持外视网膜屏障的完整性。pEYS611还保护光感受器免受N-甲基-N-亚硝基脲诱导的凋亡。最后，在RP的RCS大鼠模型中，pEYS611延缓了结构和功能退化，同时作为氧化应激生物标志物的眼内丙二醛（MDA）含量降低。TF非病毒基因递送在视网膜退行性疾病模型中的神经保护益处进一步验证了铁过载作为治疗靶点，并支持继续开发pEY611用于治疗RP和干性AMD。
