Long-term Retinal Function and Structure Rescue Using Capsid Mutant AAV8 Vector in the rd10 Mouse, a Model of Recessive Retinitis Pigmentosa
Long-term Retinal Function and Structure Rescue Using Capsid Mutant AAV8 Vector in the rd10 Mouse, a Model of Recessive Retinitis Pigmentosa
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DOI：
10.1038/mt.2010.273
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发表时间：
2011-02-01
影响因子：
12.4
通讯作者：
Hauswirth, William W.
中科院分区：
文献类型：
--
作者：
Pang, Ji-jing;Dai, Xufeng;Hauswirth, William W.
视网膜变性10（rd 10）小鼠是常染色体隐性视网膜色素变性（RP）的良好表征模型，其在视杆cGMP-磷酸二酯酶（PDE β）的β亚基中携带自发突变。Rd 10小鼠表现出光感受器功能障碍和快速的视杆细胞变性，随后是视锥细胞变性和内层视网膜的重塑。在这里，我们评估是否使用快速作用的酪氨酸衣壳突变体AAV 8（Y 733 F）的基因置换可以提供长期治疗在这个模型中。将AAV 8（Y 733 F）-smCBA-PDE β视网膜下递送至出生后第14天（P14）rd 10小鼠的仅一只眼睛。注射后6个月，光谱域光学相干断层扫描（SD-OCT）、视网膜电图（ERG）、视动行为测试和免疫组织化学显示，AAV 8（Y 733 F）介导的PDE β表达恢复了视网膜功能和视觉行为，并在治疗的rd 10眼中保留了视网膜结构至少6个月。这是在PDE β-RP动物模型中首次证明通过基因治疗进行长期表型挽救。它也是酪氨酸衣壳突变体AAV 8（Y 733 F）介导的视网膜表型校正的第一个实例。这些结果为PDE beta-RP基因治疗试验的发展奠定了基础，并表明酪氨酸-衣壳突变体AAV载体可能对治疗其他快速变性的视网膜变性模型有效。
The retinal degeneration 10 (rd10) mouse is a well-characterized model of autosomal recessive retinitis pigmentosa (RP), which carries a spontaneous mutation in the beta subunit of rod cGMP-phosphodiesterase (PDE beta). Rd10 mouse exhibits photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration and remodeling of the inner retina. Here, we evaluate whether gene replacement using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can provide long-term therapy in this model. AAV8 (Y733F)-smCBA-PDE beta was subretinally delivered to postnatal day 14 (P14) rd10 mice in one eye only. Six months after injection, spectral domain optical coherence tomography (SD-OCT), electroretinogram (ERG), optomotor behavior tests, and immunohistochemistry showed that AAV8 (Y733F)-mediated PDE beta expression restored retinal function and visual behavior and preserved retinal structure in treated rd10 eyes for at least 6 months. This is the first demonstration of long-term phenotypic rescue by gene therapy in an animal model of PDE beta-RP. It is also the first example of tyrosine-capsid mutant AAV8 (Y733F)-mediated correction of a retinal phenotype. These results lay the groundwork for the development of PDE beta-RP gene therapy trial and suggest that tyrosine-capsid mutant AAV vectors may be effective for treating other rapidly degenerating models of retinal degeneration.