Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat−/− mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat−/− mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat−/− animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.

中文翻译：

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眼内和静脉内基因联合递送治疗脉络膜和视网膜回旋萎缩


脉络膜和视网膜回旋萎缩 （GACR） 是由于鸟氨酸氨基转移酶 （OAT） 缺乏症，导致高鸟氨酸血症，导致视网膜色素上皮，然后是脉络膜和视网膜变性。腺相关病毒血清型 8 （AAV8） 载体介导的 OAT （AAV8-OAT） 肝脏基因转移可降低 GACR 的 Oat−/− 小鼠模型中的鸟氨酸血症，并改善视网膜功能和结构。由于 OAT 在包括视网膜在内的各种组织中表达，我们研究了恢复视网膜或肝脏或两者组织中 OAT 表达对 Oat −/− 小鼠视网膜表型的疗效。静脉内和视网膜下给药 AAV8-OAT 导致静脉内 AAV8-OAT 给药后眼内和肝脏 OAT 表达，鸟氨酸血症降低，而仅在联合基因递送后眼内鸟氨酸水平显著降低。因此，只有接受静脉内和视网膜下 AAV8-OAT 联合给药的 Oat-/− 动物在视网膜形态和功能方面表现出显着改善。这项工作显示了肝脏和视网膜 OAT 联合补充剂治疗 GACR 的益处。