WN1316, A Novel Anti-Oxidant Compound for the Treatment of Leber's Hereditary Optic Neuropathy (LHON)

Abstract

Leber’s Hereditary Optic Neuropathy (LHON) is a devastating mitochondrial disorder that leads to irreversible blindness. A mutation in the mitochondrial ND4 gene causes the majority of cases. Oxidative stress plays a role in disease pathology. WN1316 is a small molecule compound with potent anti-oxidant properties. Using in vitro and in vivo assays, the effectiveness of WN1316 in the treatment of LHON was tested. In vitro, the neuroprotective effects of WN1316 were tested against the oxidative stressors menadione and H2O2. These studies showed that WN1316 can protect SH-SY5Y neuronal cells and 661W photoreceptor-derived cells from oxidative stress in a concentration-dependent manner. Combination therapies with WN1316 and the X-linked Inhibitor of Apoptosis (XIAP) provided even better protection. In vivo, LHON disease had not progressed sufficiently to assess WN1316 effects on retinal function and axon counts. However we saw some delay in disease progression in the WN1316 group using electron microscopy. These initial studies suggest that WN1316 will be effective in the treatment of LHON, but we need to increase the timeline for disease progression to see the full effects of the compound.