Treatment of Leber’s hereditary optic neuropathy patients with EPI-743 prevents decline of the serum biomarker - neuron specific enolase

Abstract

Purpose: Neuron specific enolase (NSE) is a glycolytic enzyme found in mature neurons of the central nervous system. Retinal ganglion cells (RGC) degenerate in Leber’s hereditary optic neuropathy (LHON). We sought to compare NSE levels in LHON patients receiving an experimental treatment, EPI-743, to non-LHON subjects, LHON affected and LHON carriers.

Methods: Twelve patients carrying one of the three common LHON mutations (mt11778, mt3460 and mt14484) were enrolled in an open label clinical trial of the experimental drug EPI-743 that is in clinical development for mitochondrial diseases. Serum was collected at each clinic visit and stored at -80^oC. Serum samples were slowly thawed in 4^oC before each NSE assay. Enzyme-linked immunosorbent assay was used to determine NSE levels. These results were compared to normal controls (n=14), LHON affected (n=15), and carriers (n=46 - previously described Brazilian mt11778 pedigree and off-pedigree; Yee et al, IOVS 2012).

Results: Pretreatment NSE levels in LHON patients (n=6) were 9.4ug/ml. Following treatment, LHON patients had NSE level of 9.26ug/ml (range 6.21 - 12.64) and 9.01ug/ml (range 6.87 - 12.86) at about 12 (n=12; P=0.43) and 18 months (n=6; P=0.74) of EPI-743, respectively. There were no differences in subgroup analysis in NSE levels between mutation type. NSE levels from controls, affected LHON patients not on treatment and carriers were 6.2ug/ml, 5.9ug/ml and 27.17ug/ml, respectively. There was a significant difference between affected LHON patients not on treatment and the following: patients treated with EPI-743 at 12 (P≤ 0.05) and 18 months (P≤ 0.05).

Conclusions: Over the time period evaluated, EPI-743 stabilizes NSE levels in LHON patients and alters the predicted decline of NSE levels observed with disease progression. NSE levels in untreated affected LHON patients are significantly lower compared to treated patients even after 18 months of treatment. This may be explained by EPI-743 preserving RGCs capable of releasing NSE. Future studies will help discriminate between this preservation effect and the possibility that EPI-743 upregulates NSE synthesis or promotes NSE release.

Keywords: 613 neuro-ophthalmology: optic nerve • 600 mitochondria • 759 visual impairment: neuro-ophthalmological disease