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首页> 外文OA文献 >Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors
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Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors

机译：因AIPL1缺陷引起的色素性视网膜炎和Leber先天性黑桃病的基因治疗：使用AAV2 / 2和AAV2 / 8载体有效挽救部分和完全Aipl1缺乏症的小鼠模型

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摘要

Defects in the photoreceptor-specific gene encoding aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) are clinically heterogeneous and present as Leber Congenital Amaurosis, the severest form of early-onset retinal dystrophy and milder forms of retinal dystrophies such as juvenile retinitis pigmentosa and dominant cone-rod dystrophy. [Perrault, I., Rozet, J.M., Gerber, S., Ghazi, I., Leowski, C., Ducroq, D., Souied, E., Dufier, J.L., Munnich, A. and Kaplan, J. (1999) Leber congenital amaurosis. Mol. Genet. Metab., 68, 200–208.] Although not yet fully elucidated, AIPL1 is likely to function as a specialized chaperone for rod phosphodiesterase (PDE). We evaluate whether AAV-mediated gene replacement therapy is able to improve photoreceptor function and survival in retinal degeneration associated with AIPL1 defects. We used two mouse models of AIPL1 deficiency simulating three different rates of photoreceptor degeneration. The Aipl1 hypomorphic (h/h) mouse has reduced Aipl1 levels and a relatively slow degeneration. Under light acceleration, the rate of degeneration in the Aipl1 h/h mouse is increased by 2–3-fold. The Aipl1−/− mouse has no functional Aipl1 and has a very rapid retinal degeneration. To treat the different rates of degeneration, two pseudotypes of recombinant adeno-associated virus (AAV) exhibiting different transduction kinetics are used for gene transfer. We demonstrate restoration of cellular function and preservation of photoreceptor cells and retinal function in Aipl1 h/h mice following gene replacement therapy using an AAV2/2 vector and in the light accelerated Aipl1 h/h model and Aipl1−/− mice using an AAV2/8 vector. We have thus established the potential of gene replacement therapy in varying rates of degeneration that reflect the clinical spectrum of disease. This is the first gene replacement study to report long-term rescue of a photoreceptor-specific defect and to demonstrate effective rescue of a rapid photoreceptor degeneration.
机译：编码与芳烃受体相互作用的蛋白样1（AIPL1）的感光器特异性基因中的缺陷在临床上是异质的，并表现为Leber先天性阿默病，这是最严重的早期视网膜营养不良和较轻度的视网膜营养不良，例如青少年视网膜色素变性和显性锥体棒营养不良。 [Perrault，I.，Rozet，JM，Gerber，S.，Ghazi，I.，Leowski，C.，Ducroq，D.，Souied，E.，Dufier，JL，Munnich，A.和Kaplan，J.（1999 ）莱伯先天性黑皮肤。大声笑基因[Metab。，68，200–208。]尽管尚未完全阐明，但AIPL1可能充当杆状磷酸二酯酶（PDE）的专门伴侣。我们评估是否AAV介导的基因替代疗法能够改善与AIPL1缺陷相关的视网膜变性中的光感受器功能和存活。我们使用AIPL1缺乏症的两个小鼠模型来模拟三种不同的感光细胞变性速率。 Aipl1亚型（h / h）鼠标具有降低的Aipl1水平和相对较慢的变性。在光加速下，Aipl1 h / h小鼠的退化率增加了2-3倍。 Aipl1-/-小鼠没有功能性Aipl1，并且视网膜变性非常迅速。为了治疗不同程度的变性，将具有不同转导动力学的两种假型重组腺相关病毒（AAV）用于基因转移。我们证明了在使用AAV2 / 2载体进行基因替代治疗后，在Aipl1 h / h小鼠中，在光加速的Aipl1 h / h模型中，以及在Aipl1-/-小鼠中，使用AAV2 / 2，细胞功能恢复以及感光细胞和视网膜功能的保存8矢量。因此，我们已经确立了基因替代疗法在反映疾病临床范围的不同变性率中的潜力。这是第一个报告长期挽救感光细胞特异性缺陷并证明有效挽救快速感光细胞变性的基因替代研究。

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