Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina
Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina
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DOI：
10.1016/j.exer.2006.12.019
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发表时间：
2007-04-01
影响因子：
3.4
通讯作者：
Aguirre, Gustavo D.
中科院分区：
文献类型：
--
作者：
Beltran, William A.;Wen, Rong;Aguirre, Gustavo D.
睫状神经营养因子（CNTF）在几种视网膜变性的动物模型中挽救光感受器，目前正在评估其作为人类视网膜色素变性的潜在治疗方法。本研究旨在检测CNTF是否能预防XLPRA2中的感光细胞损失，XLPRA2是由RPGR外显子ORF 15中的移码突变引起的X连锁视网膜色素变性的早发犬模型。在XLPRA2犬中测试了CNTF的四种不同治疗方案。在麻醉下，在不同年龄的动物左眼接受玻璃体内注射12 μ g CNTF。右眼作为对照，注射相似体积的磷酸盐缓冲盐水（PBS）。给药期间定期进行眼部检查。处死时，对犬实施安乐死，采集眼睛，并处理视网膜，以包埋在最佳切割温度（OCT）介质中。在H&E切片上评价外核层（ONL）厚度，并比较CNTF和PBS治疗眼的值。周边视网膜的形态学改变，其特征在于使用细胞特异性标记的免疫组织化学。在半薄塑料切片上检查视网膜中的细胞增殖，并在冷冻切片上通过BrdU脉冲标记和Ki67免疫组织化学检查。所有CNTF治疗的眼睛都表现出角膜上皮病、囊下白内障和葡萄膜炎的早期临床体征。在CNTF和PBS注射的眼睛之间，ONL厚度没有统计学显著差异。在CNTF治疗眼的外周视网膜中观察到显著的视网膜重塑，包括杆数量的异常增加，以及一些杆、锥、双极和Muller细胞的错位。这仅在犬视网膜达到完全成熟的年龄之前注射CNTF时可见。在XLPRA2犬中，玻璃体内注射CNTF未能阻止感光细胞在中央和中周边视网膜中发生细胞死亡。CNTF还引起眼部副作用和与细胞去分化和增殖一致的外周形态学改变。我们的研究结果表明，某些遗传形式的视网膜变性可能对CNTF的神经保护作用没有反应。(c)2006爱思唯尔有限公司保留所有权利。
Ciliary neurotrophic factor (CNTF) rescues photoreceptors in several animal models of retinal degeneration and is currently being evaluated as a potential treatment for retinitis pigmentosa in humans. This study was conducted to test whether CNTF prevents photoreceptor cell loss in XLPRA2, an early onset canine model of X-linked retinitis pigmentosa caused by a frameshift mutation in RPGR exon ORF15. Four different treatment regimens of CNTF were tested in XLPRA2 dogs. Under anesthesia, the animals received at different ages an intravitreal injection of 12 mu g of CNTF in the left eye. The right eye served as a control and was injected with a similar volume of phosphate buffered saline (PBS). Ocular examinations were performed regularly during the treatment periods. At termination, the dogs were euthanatized, eyes collected and the retinas were processed for embedding in optimal cutting temperature (OCT) medium. The outer nuclear layer (ONL) thickness was evaluated on H&E sections and values in both CNTF- and PBS-treated eyes were compared. Morphologic alterations in the peripheral retina were characterized by immunohistochemistry using cell-specific markers. Cell proliferation in the retinas was examined on semi-thin plastic sections, and by BrdU pulse-labeling and Ki67 immunohistochemistry on cryosections. All CNTF-treated eyes showed early clinical signs of corneal epitheliopathy, subcapsular cataracts and uveitis. No statistically significant difference in ONL thickness was seen between the CNTF- and PBS-injected eyes. Prominent retinal remodeling that consisted in an abnormal increase in the number of rods, and in misplacement of some rods, cones, bipolar and Muller cells, was observed in the peripheral retina of CNTF-treated eyes. This was only seen when CNTF was in injected before the age at which the canine retina reaches full maturation. In XLPRA2 dogs, intravitreal injections of CNTF failed to prevent photoreceptors from undergoing cell death in the central and mid-peripheral retina. CNTF also caused ocular side-effects and morphologic alterations in the periphery that were consistent with cell dedifferentiation and proliferation. Our findings suggest that some inherited forms of retinal degeneration may not respond to CNTF's neuroprotective effects. (c) 2006 Elsevier Ltd. All rights reserved.