Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics
Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics
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DOI：
10.1073/pnas.0807027105
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发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Hauswirth, William W.
中科院分区：
文献类型：
--
作者：
Cideciyan, Artur V.;Aleman, Tomas S.;Hauswirth, William W.
RPE 65基因编码类维生素A循环的异构酶，这是哺乳动物视觉的酶促途径。RPE 65的突变会破坏类维生素A循环，导致先天性人类失明，称为Leber先天性黑蒙（LCA）。我们使用基于腺相关病毒2的RPE 65基因替代疗法治疗三名患有RPE 65-LCA的年轻人，并在干预前和干预后90天内测量他们的视力。所有三名患者在治疗后30天显示出视觉灵敏度的统计学显著增加，这些视觉灵敏度局限于接受载体的视网膜区域。在30至90天之间，效果没有变化。在治疗区域中可以证明基于视锥和视杆细胞的视觉。对于锥体，有高达1.7个对数单位的增加（即，50倍）;而对于杆，有高达4.8个对数单位的增益（即，63，000倍）。为了评估基因治疗恢复了多大比例的全视力潜力，我们将治疗区域内剩余光感受器的水平与光敏感度相关联。我们发现，干预可以克服几乎所有的光敏感性损失所造成的生化封锁。然而，这种重建的维甲酸循环并不完全正常。新处理的视杆细胞的再敏感动力学明显缓慢，需要8小时或更长时间才能达到完全敏感性，与对照组相比，
The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with