Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats
Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats
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DOI：
10.1038/sj.gt.3302028
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发表时间：
2003-08-01
期刊：
影响因子：
5.1
通讯作者：
Sueishi, K
中科院分区：
文献类型：
--
作者：
Miyazaki, M;Ikeda, Y;Sueishi, K
视网膜色素变性（RP）是一组异质性遗传性视网膜疾病，导致成人失明所造成的各种基因的突变。虽然很难治愈这些疾病导致的失明，但延迟疾病进展可能有很大的好处，因为大多数RP疾病发生在中年或更晚。为了测试使用神经营养因子基因的RP基因治疗策略，我们评估了猴慢病毒（SIV）介导的色素上皮衍生因子（PEDF）（一种有效的神经营养因子）视网膜下基因转移在皇家外科学院（RCS）大鼠（一种公认的RP动物模型）疾病进展过程中的作用。在所有动物中通过SIV将区域基因转移到鼻半球的外周视网膜下腔中，以监测位点特异性转基因表达以及每个视网膜中的治疗效果。lacZ和PEDF的基因转移在相应的区域色素上皮中观察到。组织学上，PEDF基因转移显着保护相应的基因转移的区域的感光细胞（PC）的损失，在实验过程中相比，对照组。PEDF对PC的抗凋亡作用可能是一种相关机制，因为与对照组相比，PEDF治疗组的末端dUTP缺口末端标记阳性PC数量显著减少（P < 0.05）。PEDF治疗的眼睛也保留了显着的敏感性，在实验过程中的闪光。这些发现清楚地表明，使用PEDF的神经保护基因治疗可以保护RP患者的视网膜变性和功能缺陷。
Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal diseases resulting in adult blindness caused by mutations of various genes. Although it is difficult to cure the blindness that results from these diseases, delaying the disease progression may be of great benefit, since the majority of RP diseases are seen in middle age or later. To test a gene therapy strategy for RP using a neurotrophic factor gene, we assessed the effect of simian lentivirus (SIV)-mediated subretinal gene transfer of pigment epithelium-derived factor (PEDF), a potent neurotrophic factor, during the disease progression in Royal College of Surgeons (RCS) rats, a well-accepted animal model of RP. Regional gene transfer via SIV into the peripheral subretinal space at the nasal hemisphere was performed in all animals to monitor site-specific transgene expression as well as the therapeutic effect in each retina. Gene transfer of lacZ and PEDF was observed in the regional pigment epithelium corresponding to the regional gene transfer. Histologically, PEDF gene transfer significantly protected the loss of photoreceptor cells (PCs) corresponding to the regions of the gene transfer, compared to those of control groups during the course of the experiment. The antiapoptotic effect of PEDF on PCs is likely to be a related mechanism, because a significant reduction of terminal dUTP-nicked end labeling-positive PC numbers was found in PEDF-treated eyes compared to those of the control group (P < 0.05). PEDF-treated eyes also retained a significant sensitivity to light flash during the experimental course. These findings clearly show that neuroprotective gene therapy using PEDF can protect retinal degeneration and functional defects in individuals with RP.