Adenoviral gene therapy with catalase suppresses experimental optic neuritis

John Guy, Xiaoping Qi, Hui Wang, William W. Hauswirth

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Objective: To determine if adenoviral-mediated transfer of the gene for catalase (CAT), the reactive oxygen species scavenger, suppresses experimental optic neuritis. Clinical Relevance: Gene therapy with CAT delivered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombinant adeno-associated viral vector is relatively slow, taking weeks to reach full levels, we studied the effects of replication- deficient adenovirus containing CAT in suppressing experimental optic neuritis. Transduction with adenovirus occurs within days of inoculation; thus, it may be more applicable for the treatment of patients with acute optic neuritis. Materials and Methods: Replication-deficient adenovirus containing CAT was injected above the right optic nerve heads of SJL/J mice that were simultaneously sensitized for experimental allergic encephalomyelitis. For controls, the left eyes were injected with the replication-deficient adenovirus without CAT or no virus. The histological effects of CAT on the lesions of experimental allergic encephalomyelitis were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), the extent of the cellular infiltrate, extravasated serum albumin labeled with immunogold (for disruption of the blood-brain barrier), and the in vivo hydrogen peroxide reaction product. Results: After 1 month, cell-specific catalase activity, evaluated by the quantitation of catalase immunogold, was increased about 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the CAT-inoculated right optic nerves compared with the control left optic nerves. The increased cellular levels of catalase reduced demyelination by 30%, optic nerve head swelling by 25%, cellular infiltration by 26%, disruption of the blood-brain barrier by 61%, and in vivo levels of hydrogen peroxide by 81%. Conclusions: Adenoviral-mediated gene transfer increased catalase levels in all optic nerve cell types, and it persisted for 1 month after inoculation. The increased cellular levels of catalase suppressed demyelination and bloodbrain barrier disruption at the loci in the optic nerve where prior magnetic resonance imaging and histopathologic studies have demonstrated the demyelinating inflammation of experimental and human optic neuritis. Together, they suggest that gene therapy with CAT may be helpful in the treatment of patients with optic neuritis.

Original languageEnglish
Pages (from-to)1533-1539
Number of pages7
JournalArchives of Ophthalmology
Volume117
Issue number11
StatePublished - Nov 1 1999
Externally publishedYes

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Optic Neuritis
Genetic Therapy
Catalase
Optic Disk
Optic Nerve
Adenoviridae
Demyelinating Diseases
Autoimmune Experimental Encephalomyelitis
Blood-Brain Barrier
Hydrogen Peroxide
Oligodendroglia
Myelin Sheath
Serum Albumin
Astrocytes
Genes
Endothelium
Axons
Reactive Oxygen Species

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Adenoviral gene therapy with catalase suppresses experimental optic neuritis. / Guy, John; Qi, Xiaoping; Wang, Hui; Hauswirth, William W.

In: Archives of Ophthalmology, Vol. 117, No. 11, 01.11.1999, p. 1533-1539.

Research output: Contribution to journalArticle

Guy, J, Qi, X, Wang, H & Hauswirth, WW 1999, 'Adenoviral gene therapy with catalase suppresses experimental optic neuritis', Archives of Ophthalmology, vol. 117, no. 11, pp. 1533-1539.
Guy, John ; Qi, Xiaoping ; Wang, Hui ; Hauswirth, William W. / Adenoviral gene therapy with catalase suppresses experimental optic neuritis. In: Archives of Ophthalmology. 1999 ; Vol. 117, No. 11. pp. 1533-1539.
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abstract = "Objective: To determine if adenoviral-mediated transfer of the gene for catalase (CAT), the reactive oxygen species scavenger, suppresses experimental optic neuritis. Clinical Relevance: Gene therapy with CAT delivered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombinant adeno-associated viral vector is relatively slow, taking weeks to reach full levels, we studied the effects of replication- deficient adenovirus containing CAT in suppressing experimental optic neuritis. Transduction with adenovirus occurs within days of inoculation; thus, it may be more applicable for the treatment of patients with acute optic neuritis. Materials and Methods: Replication-deficient adenovirus containing CAT was injected above the right optic nerve heads of SJL/J mice that were simultaneously sensitized for experimental allergic encephalomyelitis. For controls, the left eyes were injected with the replication-deficient adenovirus without CAT or no virus. The histological effects of CAT on the lesions of experimental allergic encephalomyelitis were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), the extent of the cellular infiltrate, extravasated serum albumin labeled with immunogold (for disruption of the blood-brain barrier), and the in vivo hydrogen peroxide reaction product. Results: After 1 month, cell-specific catalase activity, evaluated by the quantitation of catalase immunogold, was increased about 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the CAT-inoculated right optic nerves compared with the control left optic nerves. The increased cellular levels of catalase reduced demyelination by 30{\%}, optic nerve head swelling by 25{\%}, cellular infiltration by 26{\%}, disruption of the blood-brain barrier by 61{\%}, and in vivo levels of hydrogen peroxide by 81{\%}. Conclusions: Adenoviral-mediated gene transfer increased catalase levels in all optic nerve cell types, and it persisted for 1 month after inoculation. The increased cellular levels of catalase suppressed demyelination and bloodbrain barrier disruption at the loci in the optic nerve where prior magnetic resonance imaging and histopathologic studies have demonstrated the demyelinating inflammation of experimental and human optic neuritis. Together, they suggest that gene therapy with CAT may be helpful in the treatment of patients with optic neuritis.",
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N2 - Objective: To determine if adenoviral-mediated transfer of the gene for catalase (CAT), the reactive oxygen species scavenger, suppresses experimental optic neuritis. Clinical Relevance: Gene therapy with CAT delivered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombinant adeno-associated viral vector is relatively slow, taking weeks to reach full levels, we studied the effects of replication- deficient adenovirus containing CAT in suppressing experimental optic neuritis. Transduction with adenovirus occurs within days of inoculation; thus, it may be more applicable for the treatment of patients with acute optic neuritis. Materials and Methods: Replication-deficient adenovirus containing CAT was injected above the right optic nerve heads of SJL/J mice that were simultaneously sensitized for experimental allergic encephalomyelitis. For controls, the left eyes were injected with the replication-deficient adenovirus without CAT or no virus. The histological effects of CAT on the lesions of experimental allergic encephalomyelitis were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), the extent of the cellular infiltrate, extravasated serum albumin labeled with immunogold (for disruption of the blood-brain barrier), and the in vivo hydrogen peroxide reaction product. Results: After 1 month, cell-specific catalase activity, evaluated by the quantitation of catalase immunogold, was increased about 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the CAT-inoculated right optic nerves compared with the control left optic nerves. The increased cellular levels of catalase reduced demyelination by 30%, optic nerve head swelling by 25%, cellular infiltration by 26%, disruption of the blood-brain barrier by 61%, and in vivo levels of hydrogen peroxide by 81%. Conclusions: Adenoviral-mediated gene transfer increased catalase levels in all optic nerve cell types, and it persisted for 1 month after inoculation. The increased cellular levels of catalase suppressed demyelination and bloodbrain barrier disruption at the loci in the optic nerve where prior magnetic resonance imaging and histopathologic studies have demonstrated the demyelinating inflammation of experimental and human optic neuritis. Together, they suggest that gene therapy with CAT may be helpful in the treatment of patients with optic neuritis.

AB - Objective: To determine if adenoviral-mediated transfer of the gene for catalase (CAT), the reactive oxygen species scavenger, suppresses experimental optic neuritis. Clinical Relevance: Gene therapy with CAT delivered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombinant adeno-associated viral vector is relatively slow, taking weeks to reach full levels, we studied the effects of replication- deficient adenovirus containing CAT in suppressing experimental optic neuritis. Transduction with adenovirus occurs within days of inoculation; thus, it may be more applicable for the treatment of patients with acute optic neuritis. Materials and Methods: Replication-deficient adenovirus containing CAT was injected above the right optic nerve heads of SJL/J mice that were simultaneously sensitized for experimental allergic encephalomyelitis. For controls, the left eyes were injected with the replication-deficient adenovirus without CAT or no virus. The histological effects of CAT on the lesions of experimental allergic encephalomyelitis were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), the extent of the cellular infiltrate, extravasated serum albumin labeled with immunogold (for disruption of the blood-brain barrier), and the in vivo hydrogen peroxide reaction product. Results: After 1 month, cell-specific catalase activity, evaluated by the quantitation of catalase immunogold, was increased about 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the CAT-inoculated right optic nerves compared with the control left optic nerves. The increased cellular levels of catalase reduced demyelination by 30%, optic nerve head swelling by 25%, cellular infiltration by 26%, disruption of the blood-brain barrier by 61%, and in vivo levels of hydrogen peroxide by 81%. Conclusions: Adenoviral-mediated gene transfer increased catalase levels in all optic nerve cell types, and it persisted for 1 month after inoculation. The increased cellular levels of catalase suppressed demyelination and bloodbrain barrier disruption at the loci in the optic nerve where prior magnetic resonance imaging and histopathologic studies have demonstrated the demyelinating inflammation of experimental and human optic neuritis. Together, they suggest that gene therapy with CAT may be helpful in the treatment of patients with optic neuritis.

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