Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of inherited retinal degeneration
Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of inherited retinal degeneration
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DOI：
10.1038/sj.gt.3300440
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发表时间：
1997-07-01
期刊：
影响因子：
5.1
通讯作者：
Jones, SE
中科院分区：
文献类型：
--
作者：
Jomary, C;Vincent, KA;Jones, SE
对导致遗传性视网膜变性的突变的认识为体细胞基因治疗的发展提供了基础，在体细胞基因治疗中，潜在的矫正基因被转移到靶感光细胞。为此，我们已经评估了重组腺相关病毒（AAV）载体在rd小鼠视网膜中递送和表达cGMP磷酸二酯酶-β（PDE-β）基因的正确形式的功效，所述rd小鼠由于内源基因的隐性突变而遭受快速视网膜变性。使用截短的鼠视蛋白启动子来驱动PDE-β cDNA的表达。眼内注射AAV. PDE-β后，观察到免疫反应性PDE蛋白的视网膜表达增加，包括在感光细胞体内。与年龄匹配的对照组相比，治疗的眼睛表现出增加的光感受器数量和两倍的增加，在体外视网膜电图测量的光敏感性。这些发现提供了证据，功能性感光神经元的拯救可以通过体细胞基因治疗实现。
Knowledge of the mutations leading to inherited retinal degenerations provides a foundation for the development of somatic gene therapy in which potentially corrective genes are transferred to the target photoreceptor cells. Towards this end, we have evaluated the efficacy of a recombinant adeno-associated virus (AAV) vector to deliver and express the correct form of the cGMP phosphodiesterase-beta (PDE-beta) gene in the retinas of rd mice, which suffer rapid retinal degeneration due to recessive mutation in the endogenous gene. A truncated murine opsin promoter was used to drive expression of the PDE-beta cDNA. Following intraocular injection of AAV.PDE-beta, increased retinal expression of immunoreactive PDE protein was observed including within photoreceptor cell bodies. Compared with age-matched controls, treated eyes showed increased numbers of photoreceptors and a twofold increase in sensitivity to light as measured by in vitro electroretinography. These findings provide evidence that rescue of functional photoreceptor neurons can be achieved by somatic gene therapy.