Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa
Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa
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DOI：
10.1016/j.exer.2008.05.016
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发表时间：
2008-09-01
影响因子：
3.4
通讯作者：
Flannery, John G.
中科院分区：
文献类型：
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作者：
Guerin, K.;Gregory-Evans, C. Y.;Flannery, John G.
我们研究了系统给药氨基糖苷作为一种治疗视网膜变性导致过早终止密码子（PTC）突变的潜力。氨基糖苷类被系统地递送到两种啮齿动物视网膜变性模型：一种由视紫红质PTC引起的显性疾病的转基因大鼠模型（S334ter）；以及由类视黄醇异构酶Rpe65中的PTC引起的隐性疾病（rd12）小鼠模型。进行初始荧光素酶报告基因测定，以测量庆大霉素诱导的体外读透的效率。这些实验表明，庆大霉素治疗在体外诱导了平均5.3%的额外读透S334ter PTC，但不影响rd12 PTC。从出生后第5天开始，动物每天接受一定剂量的庆大霉素或遗传素皮下注射。通过组织病理学和视网膜电图（ERG）检查治疗对视网膜变性的影响。在几周的治疗中，氨基糖苷全身治疗显著增加了S334ter大鼠模型中存活的光感受器数量，但对减缓rd12小鼠模型中的视网膜变性没有效果。同样，ERG记录显示，处理过的S334ter大鼠的视网膜功能得到了更好的保存，但在rd12小鼠中没有观察到差异。每日皮下注射12.5 μ g/g庆大霉素是唯一抑制视网膜变性且无明显全身不良副作用的方案。庆大霉素-德克萨斯红（GTTR）偶联实验显示，出生后第50天以后，药物的有效性降低与药物的眼部渗透降低相关。我们得出结论，在大鼠模型中，类似于5%的异常截断蛋白减少足以提高光感受器的存活率。这种截断蛋白的变化与氨基糖苷在其他非眼动物模型中使用时所见的有益效果一致。在rd12小鼠中，尽管这种特殊的PTC理论上对氨基糖苷修饰更敏感，但缺乏疗效。我们的结论是，ptc在体内和体外的氨基糖苷读通不能仅仅从基因组背景来预测。由于视网膜变性存在相当大的遗传异质性，非基因特异性的药物治疗具有重要的吸引力。我们的研究结果表明，如果能够克服全身毒性和有限的眼穿透等不良问题，小分子疗法，如氨基糖苷类，靶向突变类，作为视网膜疾病的治疗方法可能具有相当大的潜力。(C) 2008 Elsevier Ltd版权所有。
We studied the potential of systemically administered aminoglycosides as a therapy for retinal degeneration resulting from premature termination codon (PTC) mutations. Aminoglycosides were systemically delivered to two rodent models of retinal degeneration: a transgenic rat model of dominant disease caused by a PTC in rhodopsin (S334ter); and a mouse model of recessive disease (rd12) caused by a PTC in the retinoid isomerase Rpe65. Initial luciferase reporter assays were undertaken to measure the efficiency of gentamicin-induced read-through in vitro. These experiments indicated that gentamicin treatment induced on average a 5.3% extra read-through of the S334ter PTC in vitro, but did not affect the rd12 PTC. Beginning at postnatal day 5, animals received daily subcutaneous injections of gentamicin or geneticin at a range of doses. The effect of the treatment on retinal degeneration was examined by histopathology and electroretinography (ERG). Systemic treatment with aminoglycoside significantly increased the number of surviving photoreceptors in the S334ter rat model over several weeks of treatment, but was not effective in slowing the retinal degeneration in the rd12 mouse model. Similarly, ERG recordings indicated better preservation of retinal function in the treated S334ter rats, but no difference was observed in the rd12 mice. Daily subcutaneous injection of 12.5 mu g/g gentamicin was the only regimen that inhibited retinal degeneration without apparent adverse systemic side effects. Reduced effectiveness beyond postnatal day 50 correlated with reduced ocular penetration of drug as seen in gentamicin-Texas red (GTTR) conjugation experiments. We conclude that, in the rat model, an similar to 5% reduction of abnormal truncated protein is sufficient to enhance photoreceptor survival. Such a change in truncated protein is consistent with beneficial effects seen when aminoglycosides has been used in other, non-ocular animal models. In the rd12 mouse, lack of efficacy was seen despite this particular PTC being theoretically more sensitive to aminoglycoside modification. We conclude that aminoglycoside readthrough of PTCs in vitro and in vivo cannot be predicted just from genomic context. Because there is considerable genetic heterogeneity amongst retinal degenerations, pharmacologic therapies that are not gene-specific have significant appeal. Our findings suggest that if adverse issues such as systemic toxicity and limited ocular penetration can be overcome, small molecule therapeutics, Such as aminoglycosides, which target classes of mutation could hold considerable potential as therapies for retinal disease. (C) 2008 Elsevier Ltd. All rights reserved.