CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa. Mol Ther 2015 Aug;23(8):1308-1319
Date
04/22/2015Pubmed ID
25896245Pubmed Central ID
PMC4539573DOI
10.1038/mt.2015.68Scopus ID
2-s2.0-84938420570 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
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.
Author List
Lipinski DM, Barnard AR, Singh MS, Martin C, Lee EJ, Davies WIL, MacLaren REAuthor
Daniel M. Lipinski PhD Associate Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCiliary 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
