title: CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa.
abstract: 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.
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Lipinski
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Alun R
authors.initials: AR
authors.lastname: Barnard
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Mandeep S
authors.initials: MS
authors.lastname: Singh
authors.affiliation: Department of Psychology, The University of Sheffield, Sheffield, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Martin
authors.affiliation: Moorfields Eye Hospital & UCL NIHR Biomedical Research Centre for Ophthalmology, London, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; School of Animal Biology and University of Western Australia Oceans Institute, University of Western Australia, Perth, Australia.
authors.forename: Wayne I L
authors.initials: WIL
authors.lastname: Davies
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Moorfields Eye Hospital & UCL NIHR Biomedical Research Centre for Ophthalmology, London, UK. Electronic address: enquiries@eye.ox.ac.uk.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
mesh_terms: D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004594:Electrophysiology; D004596:Electroretinography; D005109:Extracellular Matrix / Q000378:metabolism; D005654:Fundus Oculi; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D000066829:Neuroprotection; D012160:Retina / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D016896:Treatment Outcome; D014793:Visual Cortex / Q000473:pathology
chemical_list: D020934:Ciliary Neurotrophic Factor