Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse.
Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse.
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X连锁幼年型视网膜劈裂症（XLRS）是由视网膜劈裂素基因突变引起的神经发育异常。XLRS的特征在于通过视网膜层分裂和视觉信号的突触传递受损，导致敏锐度受损和视网膜脱离倾向。几个研究小组已经成功地使用腺相关病毒（AAV）载体治疗了鼠视网膜劈裂模型。由于XLRS视网膜的脆弱性，将这种疗法转化为临床可能需要替代侵入性视网膜下载体给药。在这里，我们表明，所有层的retinoschisin敲除（Rs1-KO）小鼠视网膜可以有效地转导与AAV载体管理简单的玻璃体注射。使用一种新的载体，使用一个3.5 kb的人视网膜分裂素启动子和一个AAV 8型衣壳，视网膜分裂素的表达被限制在神经视网膜。对Rs1-KO小鼠的玻璃体内给药导致稳健的视网膜劈裂素表达，其视网膜分布与野生型视网膜中观察到的相似，包括位于视网膜深处的光感受器的表达。未观察到脱靶表达。用该载体处理的Rs1-KO小鼠显示裂腔减少，并且通过记录应用后11 - 15周的视网膜电图来评估具有改善的视网膜信号传导。
X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection. Retinoschisin expression was restricted to the neuroretina using a new vector that uses a 3.5-kb human retinoschisin promoter and an AAV type 8 capsid. Intravitreal administration to Rs1-KO mice resulted in robust retinoschisin expression with a retinal distribution similar to that observed in wild-type retina, including the expression by the photoreceptors lying deep in the retina. No off-target expression was observed. Rs1-KO mice treated with this vector showed a decrease in the schisis cavities and had improved retinal signaling evaluated by recording the electroretinogram 11–15 weeks after the application.
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影响因子：
4.4
作者：
Takada Y;Vijayasarathy C;Zeng Y;Kjellstrom S;Bush RA;Sieving PA
通讯作者：
Sieving PA
影响因子：
2.9
作者：
Dyka, Frank M.;Wu, Winco W. H.;Molday, Robert S.
通讯作者：
Molday, Robert S.
影响因子：
4.4
作者：
Takada, Y;Fariss, RN;Sieving, PA
通讯作者：
Sieving, PA
影响因子：
5.4
作者：
Nam, Hyun-Joo;Lane, Michael Douglas;Agbandje-McKenna, Mavis
通讯作者：
Agbandje-McKenna, Mavis
影响因子：
4.1
作者：
GEORGE, NDL;YATES, JRW;MOORE, AT
通讯作者：
MOORE, AT