CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa.
CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa.
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DOI：
10.1038/mt.2015.68
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发表时间：
2015-08
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影响因子：
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通讯作者：
MacLaren RE
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文献类型：
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作者：
Lipinski DM;Barnard AR;Singh MS;Martin C;Lee EJ;Davies WIL;MacLaren RE
神经保护作为一种预防神经退行性疾病中细胞死亡的治疗策略的长期结果仍然未知，主要是由于疾病进展缓慢和评估体内神经元存活的固有困难。采用视网膜疾病的小鼠模型，我们证明睫状体神经营养因子（CNTF）赋予对光感受器变性终身保护。重复视网膜成像允许内在荧光锥光感受器的存活在体内被量化。视觉皮层成像和视觉诱发行为反应的评估表明，幸存的视锥细胞保留了功能，并向大脑发出了正确的信号。通过转录组分析探索了cntf介导的神经保护机制，揭示了蛋白质水解抑制剂的广泛上调，这可能阻止神经退行性疾病中的细胞/细胞外基质降解和补体激活。这些发现为视网膜色素变性和肌萎缩性侧索硬化症等疾病的潜在新治疗途径提供了见解，CNTF在临床试验中未被成功评估。
The long-term outcome of neuroprotection as a therapeutic strategy for preventing cell death in neurodegenerative disorders remains unknown, primarily due to slow disease progression and the inherent difficulty of assessing neuronal survival in vivo. Employing a murine model of retinal disease, we demonstrate that ciliary neurotrophic factor (CNTF) confers life-long protection against photoreceptor degeneration. Repetitive retinal imaging allowed the survival of intrinsically fluorescent cone photoreceptors to be quantified in vivo. Imaging of the visual cortex and assessment of visually-evoked behavioural responses demonstrated that surviving cones retain function and signal correctly to the brain. The mechanisms underlying CNTF-mediated neuroprotection were explored through transcriptome analysis, revealing widespread up-regulation of proteolysis inhibitors, which may prevent cellular/extracellular matrix degradation and complement activation in neurodegenerative diseases. These findings provide insights into potential novel therapeutic avenues for diseases such as retinitis pigmentosa and amyotrophic lateral sclerosis, for which CNTF has been evaluated unsuccessfully in clinical trials.