Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa
Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa
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DOI：
10.1006/mthe.2001.0473
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发表时间：
2001-11-01
影响因子：
12.4
通讯作者：
Bennett, J
中科院分区：
文献类型：
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作者：
Liang, FQ;Aleman, TS;Bennett, J
本研究旨在确定玻璃体内注射携带睫状神经营养因子（CNTF）的腺相关病毒（AAV）是否能在色素性视网膜炎动物模型中实现光感受器的长期形态学和生理学挽救，以及在变性开始后注射这种病毒是否能有效保护剩余的光感受器。我们在出生后早期的Prph2(Rd2/Rd2)（以前称为rds/rds）小鼠以及成年的P23H和S334ter视蛋白转基因大鼠中玻璃体内注射rAAV.CNTF.GFP。对侧眼睛接受玻璃体内注射rAAV.GFP或假注射。我们在感染后6个月（大鼠）和8.5至9个月（小鼠）对眼睛进行评估，并寻找光感受器挽救和CNTF - GFP表达的组织学和视网膜电图（ERG）证据。玻璃体内注射rAAV导致Prph2(Rd2/Rd2)视网膜中的视网膜神经节细胞以及突变大鼠视网膜中的神经节细胞、米勒细胞和水平/无长突细胞高效转导。转基因表达定位于最接近注射部位的视网膜区域。我们在所有接受rAAV.CNTF.GFP的动物眼睛中观察到光感受器有显著的形态学保护。我们发现在离表达CNTF - GFP的细胞最远的区域保护作用最强。Prph2(Rd2/Rd2)的视网膜电图未显示眼间差异。接受rAAV.CNTF.GFP的大鼠模型眼睛的视网膜电图振幅比接受rAAV.GFP的眼睛低。功能和结构结果的不一致，特别是在大鼠模型中，表明在考虑人类应用之前需要更好地理解CNTF的作用机制。
The present study aimed to determine whether intravitreal administration of an adeno-associated virus (AAV) carrying ciliary neurotrophic factor (CNTF) can achieve long-term morphological and physiological rescue of photoreceptors in animal models of retinitis pigmentosa, and whether injection of this virus after degeneration begins is effective in protecting the remaining photoreceptors. We injected rAAV.CNTF.GFP intravitreally in early postnatal Prph2(Rd2/Rd2) (formerly rds/rds) mice and in adult P23H and S334ter rhodopsin transgenic rats. Contralateral eyes received an intravitreal injection of rAAV.GFP or a sham injection. We evaluated the eyes at 6 months (rats) and 8.5 to 9 months (mice) postinfection and looked for histological and electoretinographic (ERG) evidence of photoreceptor rescue and CNTF-GFP expression. Intravitreal administration of rAAV resulted in efficient transduction of retinal ganglion cells in the Prph2(Rd2/Rd2) retina, and ganglion, Muller, and horizontal/amacrine cells in the mutant rat retinas. Transgene expression localized to the retinal region closest to the injection site. We observed prominent morphological protection of photoreceptors in the eyes of all animals receiving rAAV.CNTF.GFP. We found the greatest protection in regions most distant from the CNTF-GFP-expressing cells. The Prph2(Rd2/Rd2) ERGS did not exhibit interocular differences. Eyes of the rat models administered rAAV.CNTF.GFP had lower ERG amplitudes than those receiving rAAV.GFP. The discordance of functional and structural results, especially in the rat models, points to the need for a greater understanding of the mechanism of action of CNTF before human application can be considered.