September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
WN1316, a Novel Anti-oxidant Compound for the Treatment of Leber's Hereditary Optic Neuropathy (LHON)
Author Affiliations & Notes
  • Sohair Saleem Halas
    Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • Footnotes
    Commercial Relationships   Sohair Halas, None
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Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5031. doi:
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      Sohair Saleem Halas; WN1316, a Novel Anti-oxidant Compound for the Treatment of Leber's Hereditary Optic Neuropathy (LHON). Invest. Ophthalmol. Vis. Sci. 2016;57(12):5031. doi:

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

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Purpose : A mutation in the mitochondrial gene NADH ubiquinone oxidoreductase subunit 4 (ND4) leads to the majority of cases of LHON. It is not known how this mutation leads to mitochondrial dysfunction and the apoptotic death of retinal ganglion cells (RGCs), but it is thought that oxidative stress plays a role in disease pathology. WN1316 is a small molecular compound with potent anti-oxidant properties. Using in vitro and in vivo assays, I tested the hypothesis that WN1316 will be effective in the treatment of LHON because it targets the oxidative stress pathway.

Methods : SH-SY5Y human neuroblastoma-derived cells and 661W mouse retinal photoreceptor cells were used in the in vitro studies. The neuroprotective effects of WN1316 were tested in oxidative stress-induced cell death assays (H2O2 and menadione). A two-way ANOVA was used for statistical analysis. For the in vivo studies, the LHON model was generated in DBA/1J mice by injecting adeno-associated virus expressing a mutant form of ND4 gene into the vitreous, (AAV-GFP was used as a control). Animals (N=50) were treated daily by oral gavage of 100ug/kg WN1316 for 5 months. RGC function was assessed using electroretinography (ERG). Retinal tissues were sampled for histology and immunohistochemistry. Optic nerves were sampled and analyzed by electron microscopy (EM).

Results : Treatment of SH-SY5Y cells with 10uM WN1316 significantly suppressed cell death induced by 50 uM menadione (p=0.001). WN1316 was not toxic to SH-SY5Y cells even at high concentrations (10uM). WN1316 significantly protected 661W cells from both H2O2 and menadione (p=0.005) in a dose-dependent manner. In vivo characterization of the LHON model confirmed development of a progressive disease that affects RGCs, similar to LHON in humans. Preliminary analysis of ERG, and EM of optic nerve samples reveal that WN1316 appears to delay disease progression. Histological studies are currently underway to confirm the results obtained by ERG and EM.

Conclusions : Leber’s hereditary optic neuropathy has visually devastating consequences and is without cure to date. WN1316 targets oxidative stress, which is the main pathway in the disease pathology. WN1316 shows potent neuroprotective properties in our in vitro studies, and preliminary studies in the in vivo model suggest that it will be equally effective in vivo for the treatment of LHON.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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