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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.

Original publication

DOI

10.1038/mt.2015.68

Type

Journal article

Journal

Mol Ther

Publication Date

08/2015

Volume

23

Pages

1308 - 1319

Keywords

Animals, Ciliary Neurotrophic Factor, Disease Models, Animal, Disease Progression, Electrophysiology, Electroretinography, Extracellular Matrix, Fundus Oculi, Genetic Therapy, Genetic Vectors, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Neuroprotection, Retina, Retinal Cone Photoreceptor Cells, Retinitis Pigmentosa, Sequence Analysis, RNA, Transcriptome, Treatment Outcome, Visual Cortex