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

D.M. Lipinski, A.R. Barnard, M.S. Singh, C. Martin, E.J. Lee, Wayne Davies, R.E. Maclaren

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

© The American Society of Gene & Cell Therapy. 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 languageEnglish
Pages (from-to)1308-1319
JournalMolecular Therapy
Volume23
Issue number8
Early online date2 Jun 2015
DOIs
Publication statusPublished - Aug 2015

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