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

Daniel M. Lipinski, Alun R. Barnard, Mandeep S. Singh, Chris Martin, Edward J. Lee, Wayne I.L. Davies, Robert E. MacLaren

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1308-1319
Number of pages12
JournalMolecular Therapy
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Lipinski, D. M., Barnard, A. R., Singh, M. S., Martin, C., Lee, E. J., Davies, W. I. L., & MacLaren, R. E. (2015). CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa. Molecular Therapy, 23(8), 1308-1319. https://doi.org/10.1038/mt.2015.68