Long-term suppression of neurodegeneration in chronic experimental optic neuritis: Antioxidant gene therapy

Xiaoping Qi, Liang Sun, Alfred S. Lewin, William W. Hauswirth, John Guy

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

PURPOSE. To test in mice with experimental autoimmune encephalomyelitis (EAE) a strategy designed to treat patients at risk for axonal degeneration and persistent visual loss from optic neuritis and multiple sclerosis. METHODS. The authors cloned the human extracellular superoxide dismutase (ECSOD) or catalase (CAT) gene into recombinant adenoassociated virus (AAV). Transgene expression was evaluated by immunochemistry of infected RGC-5 cells and after intravitreal injection of AAV-ECSOD or AAV-CAT, or both, into the right eyes of DBA/1J mice. Control cells and left eyes were inoculated with AAV-GFP. Animals were sensitized for EAE, followed by serial contrast-enhanced MRI for 6 months, and then were euthanatized. The effects of ECSOD and CAT modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, axonal cell loss, and retinal ganglion cell (RGC) loss. RESULTS. Western blot analysis of infected RGC-5 cells revealed that expression of ECSOD increased 15-fold and that of CAT increased 3.5-fold. One month after intraocular injections, transgene expression increased 4-fold for AAV-ECSOD and 3.3-fold for AAV-CAT. Six months after intraocular injections and EAE sensitization, combination therapy with ECSOD and catalase decreased RGC loss by 29%, optic nerve demyelination by 36%, axonal loss by 44%, and cellular infiltration by 34% compared with the contralateral control eyes inoculated with AAV-GFP. Compared with the normal optic nerve, it limited RGC loss to 9%. CONCLUSIONS. Viral-mediated delivery of antioxidant genes provides long-lasting suppression against neuronal and axonal loss associated with permanent visual disability in patients with optic neuritis and multiple sclerosis.

Original languageEnglish
Pages (from-to)5360-5370
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number12
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

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Optic Neuritis
Genetic Therapy
Retinal Ganglion Cells
Catalase
Superoxide Dismutase
Antioxidants
Viruses
Autoimmune Experimental Encephalomyelitis
Optic Nerve
Intraocular Injections
Transgenes
Multiple Sclerosis
Immunochemistry
Inbred DBA Mouse
Intravitreal Injections
Demyelinating Diseases
Myelin Sheath
Genes
Western Blotting

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Long-term suppression of neurodegeneration in chronic experimental optic neuritis : Antioxidant gene therapy. / Qi, Xiaoping; Sun, Liang; Lewin, Alfred S.; Hauswirth, William W.; Guy, John.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 12, 01.12.2007, p. 5360-5370.

Research output: Contribution to journalArticle

Qi, Xiaoping ; Sun, Liang ; Lewin, Alfred S. ; Hauswirth, William W. ; Guy, John. / Long-term suppression of neurodegeneration in chronic experimental optic neuritis : Antioxidant gene therapy. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 12. pp. 5360-5370.
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abstract = "PURPOSE. To test in mice with experimental autoimmune encephalomyelitis (EAE) a strategy designed to treat patients at risk for axonal degeneration and persistent visual loss from optic neuritis and multiple sclerosis. METHODS. The authors cloned the human extracellular superoxide dismutase (ECSOD) or catalase (CAT) gene into recombinant adenoassociated virus (AAV). Transgene expression was evaluated by immunochemistry of infected RGC-5 cells and after intravitreal injection of AAV-ECSOD or AAV-CAT, or both, into the right eyes of DBA/1J mice. Control cells and left eyes were inoculated with AAV-GFP. Animals were sensitized for EAE, followed by serial contrast-enhanced MRI for 6 months, and then were euthanatized. The effects of ECSOD and CAT modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, axonal cell loss, and retinal ganglion cell (RGC) loss. RESULTS. Western blot analysis of infected RGC-5 cells revealed that expression of ECSOD increased 15-fold and that of CAT increased 3.5-fold. One month after intraocular injections, transgene expression increased 4-fold for AAV-ECSOD and 3.3-fold for AAV-CAT. Six months after intraocular injections and EAE sensitization, combination therapy with ECSOD and catalase decreased RGC loss by 29{\%}, optic nerve demyelination by 36{\%}, axonal loss by 44{\%}, and cellular infiltration by 34{\%} compared with the contralateral control eyes inoculated with AAV-GFP. Compared with the normal optic nerve, it limited RGC loss to 9{\%}. CONCLUSIONS. Viral-mediated delivery of antioxidant genes provides long-lasting suppression against neuronal and axonal loss associated with permanent visual disability in patients with optic neuritis and multiple sclerosis.",
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N2 - PURPOSE. To test in mice with experimental autoimmune encephalomyelitis (EAE) a strategy designed to treat patients at risk for axonal degeneration and persistent visual loss from optic neuritis and multiple sclerosis. METHODS. The authors cloned the human extracellular superoxide dismutase (ECSOD) or catalase (CAT) gene into recombinant adenoassociated virus (AAV). Transgene expression was evaluated by immunochemistry of infected RGC-5 cells and after intravitreal injection of AAV-ECSOD or AAV-CAT, or both, into the right eyes of DBA/1J mice. Control cells and left eyes were inoculated with AAV-GFP. Animals were sensitized for EAE, followed by serial contrast-enhanced MRI for 6 months, and then were euthanatized. The effects of ECSOD and CAT modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, axonal cell loss, and retinal ganglion cell (RGC) loss. RESULTS. Western blot analysis of infected RGC-5 cells revealed that expression of ECSOD increased 15-fold and that of CAT increased 3.5-fold. One month after intraocular injections, transgene expression increased 4-fold for AAV-ECSOD and 3.3-fold for AAV-CAT. Six months after intraocular injections and EAE sensitization, combination therapy with ECSOD and catalase decreased RGC loss by 29%, optic nerve demyelination by 36%, axonal loss by 44%, and cellular infiltration by 34% compared with the contralateral control eyes inoculated with AAV-GFP. Compared with the normal optic nerve, it limited RGC loss to 9%. CONCLUSIONS. Viral-mediated delivery of antioxidant genes provides long-lasting suppression against neuronal and axonal loss associated with permanent visual disability in patients with optic neuritis and multiple sclerosis.

AB - PURPOSE. To test in mice with experimental autoimmune encephalomyelitis (EAE) a strategy designed to treat patients at risk for axonal degeneration and persistent visual loss from optic neuritis and multiple sclerosis. METHODS. The authors cloned the human extracellular superoxide dismutase (ECSOD) or catalase (CAT) gene into recombinant adenoassociated virus (AAV). Transgene expression was evaluated by immunochemistry of infected RGC-5 cells and after intravitreal injection of AAV-ECSOD or AAV-CAT, or both, into the right eyes of DBA/1J mice. Control cells and left eyes were inoculated with AAV-GFP. Animals were sensitized for EAE, followed by serial contrast-enhanced MRI for 6 months, and then were euthanatized. The effects of ECSOD and CAT modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, axonal cell loss, and retinal ganglion cell (RGC) loss. RESULTS. Western blot analysis of infected RGC-5 cells revealed that expression of ECSOD increased 15-fold and that of CAT increased 3.5-fold. One month after intraocular injections, transgene expression increased 4-fold for AAV-ECSOD and 3.3-fold for AAV-CAT. Six months after intraocular injections and EAE sensitization, combination therapy with ECSOD and catalase decreased RGC loss by 29%, optic nerve demyelination by 36%, axonal loss by 44%, and cellular infiltration by 34% compared with the contralateral control eyes inoculated with AAV-GFP. Compared with the normal optic nerve, it limited RGC loss to 9%. CONCLUSIONS. Viral-mediated delivery of antioxidant genes provides long-lasting suppression against neuronal and axonal loss associated with permanent visual disability in patients with optic neuritis and multiple sclerosis.

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