CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa

被引:61
作者
Lipinski, Daniel M. [1 ,2 ,3 ]
Barnard, Alun R. [1 ,2 ]
Singh, Mandeep S. [1 ,2 ]
Martin, Chris [4 ]
Lee, Edward J. [5 ,6 ]
Davies, Wayne I. L. [1 ,7 ,8 ]
MacLaren, Robert E. [1 ,2 ,5 ,6 ]
机构
[1] Univ Oxford, Nuffield Dept Clin Neurosci, Nuffield Lab Ophthalmol, Oxford OX3 9DU, England
[2] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 9DU, England
[3] Univ Florida, Dept Ophthalmol, Gainesville, FL USA
[4] Univ Sheffield, Dept Psychol, Sheffield S10 2TN, S Yorkshire, England
[5] Moorfields Eye Hosp, London, England
[6] UCL NIHR Biomed Res Ctr Ophthalmol, London, England
[7] Sch Anim Biol, Perth, WA 6009, Australia
[8] Univ Western Australia, Oceans Inst, Perth, WA 6009, Australia
基金
英国医学研究理事会; 英国惠康基金; 澳大利亚研究理事会;
关键词
CILIARY NEUROTROPHIC FACTOR; RETINAL GANGLION-CELLS; GREEN FLUORESCENT PROTEIN; VISUAL FUNCTION; PHOTORECEPTOR DEGENERATION; CONE SURVIVAL; RAT MODEL; EXPRESSION; RHODOPSIN; MICE;
D O I
10.1038/mt.2015.68
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 behavioral 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 upregulation 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.
引用
收藏
页码:1308 / 1319
页数:12
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