May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
SOD2 Gene Transfer Protects Against Optic Neuropathy Induced by a Mutant Human ND4
Author Affiliations & Notes
  • X. Qi
    University of Florida, Gainesville, Florida
    Ophthalmology,
  • L. Sun
    University of Florida, Gainesville, Florida
    Ophthalmology,
  • A. Lewin
    University of Florida, Gainesville, Florida
    Molecular Microbiology,
  • W. Hauswirth
    University of Florida, Gainesville, Florida
    Ophthalmology,
  • J. Guy
    University of Florida, Gainesville, Florida
    Ophthalmology,
  • Footnotes
    Commercial Relationships  X. Qi, None; L. Sun, None; A. Lewin, None; W. Hauswirth, None; J. Guy, None.
  • Footnotes
    Support  EY012355 and RPB
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4359. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      X. Qi, L. Sun, A. Lewin, W. Hauswirth, J. Guy; SOD2 Gene Transfer Protects Against Optic Neuropathy Induced by a Mutant Human ND4. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4359. doi: https://doi.org/.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: : - Last year, we reported that the RGC apoptosis and optic nerve degeneration induced by a mutant human ND4 (R340H) were not rescued with a normal human ND4 subunit gene, injected after induction of disease in DBA/1J mice. Since loss of RGCs and axons of the optic nerve in this mouse model were mediated by oxidative stress, here we evaluate the potential rescue effects of antioxidant gene therapy with SOD2.

Methods: : - To induce LHON we injected AAV containing a mutant ND4 subunit made compatible with the universal genetic code and containing an arginine to histidine substitution at residue 340 into both eyes of DBA/1J mice. Two days later we attempted to rescue by injecting the right eyes with AAV containing the gene for SOD2. For controls, we injected the left eyes with AAV-GFP at the same sitting. Animals were sacrificed 1 month, 3 months and 1 year later. By quantitative light and transmission electron microscopy, the differences were compared between the right eyes treated with SOD2 to the control left eyes injected with GFP, gauged by computerized analysis of optic nerve head area, myelin fiber area, axonal and retinal ganglion cell loss. Statistical analysis was performed by Student t-test for unpaired data (two-tailed).

Results: : - The ATPc mitochondrial targeting sequence directing the allotopically-expressed mutant human ND4 (R340H) into mitochondria induced optic nerve head swelling and apoptosis with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve. AAV-SOD2 scavenging of superoxide within mitochondria decreased the swelling of optic nerve head by 22% at 1 month (p=0.3). At 1 year, SOD2 treated eyes had normal optic nerve head (ONH) areas while the GFP injected control eyes exhibited ONH atrophy with the areas of 24% smaller (p=0.13). AAV-SOD2 suppressed RGC loss by 10% at 1 month (p=0.03), 16% at 3 months (p=0.02) and 31% at 1 year (p=0.05). The rescue effects of SOD2 on suppressing myelin and axonal loss were most significant among all parameters, that differences were highly statistical significant for long-term time point. Myelin loss was suppressed by 17% (p=0.0004), 22% (p=0.006), and 26% (p=0.0001), at 1, 3 and 12 months respectively. Axonal loss was reduced by 15% (p=0.04), 24% (p=0.0003), and 29% (p=0.0002) at 1, 3 and 12 months respectively.

Conclusions: : - Suppression of reactive oxygen species provides long-term protection against loss of ganglion cells in the retina and axons in the optic nerve, induced by the mutant ND4 suggesting that this form of gene therapy may be useful after the onset of disease in LHON at a time when the allotopic normal ND4 was not.

Keywords: ganglion cells • mitochondria • gene transfer/gene therapy 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×