Successful Amelioration of Mitochondrial Optic Neuropathy Using the Yeast NDI1 Gene in a Rat Animal Model

Background: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. Methodology/Principal Findings: We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects

Non-Image-Forming Light Driven Functions Are Preserved in a Mouse Model of Autosomal Dominant Optic Atrophy

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies

Effects of BAK-free travoprost treatment for 3 years in patients with normal tension glaucoma

Kenji Inoue,1 Mayumi Iwasa,1 Masato Wakakura,1 Goji Tomita21Inouye Eye Hospital, 2Toho University Ohashi Medical Center, Tokyo, JapanBackground: The purpose of this study was to evaluate the effects of benzalkonium (BAK)-free travoprost monotherapy administered for 3 years on intraocular pressure and visual field performance.Methods: The intraocular pressure of 76 patients with normal tension glaucoma was monitored every 1–3 months. A Humphrey visual field test was performed every 6 months after treatment and compared with the results before treatment. Visual field performance was also evaluated by trend and event analysis.Results: Thirty cases discontinued within 3 years. Mean intraocular pressure after 3 years of travoprost treatment (14.1 ± 2.4 mmHg) was significantly lower than that before treatment (16.8 ± 2.6 mmHg, P ‹ 0.0001). There was no change in the mean deviation and pattern standard deviation as measured by Humphrey visual field test after 3 years of treatment compared with before treatment. Visual field performance was worse in one patient (2.8%) by trend analysis and five patients (13.9%) by event analysis. Treatment was discontinued in six cases (7.9%) due to the appearance of adverse reactions.Conclusion: BAK-free travoprost monotherapy was effective in reducing intraocular pressure for at least 3 years; however, visual field performance worsened in 2.8%–13.9% of patients with normal tension glaucoma.Keywords: BAK-free travoprost, intraocular pressure, visual field, trend analysis, event analysi

Effects of unoprostone on diurnal variation of intraocular pressure in healthy volunteers

Kenji Inoue1, Kei Noguchi1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, Tokyo; 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanPurpose: To prospectively evaluate the diurnal variation of intraocular pressure (IOP) during unoprostone treatment in 13 healthy volunteers.Method: IOP was measured by Goldmann applanation tonometry by the same observer every 3 hours from 9 am to 9 am the next morning. Unoprostone was then instilled at 9 am and 9 pm daily for 1 month. After 1 month, IOP was measured again with unoprostone instilled at 9 am and 9 pm during IOP measurement. We then compared the average daily IOP before and after the treatment (paired t-test).Results: After 1 month of treatment, the average IOP decreased at every time point but one (12 pm, 3 pm, 6 pm, 9 pm, 12 am, 3 am, and 9 am, but not at 6 am). There were no adverse reactions and none of the subjects discontinued unoprostone.Conclusion: The hypotensive effects of unoprostone persist throughout the day, but this study suggests that the effects may be weaker at nighttime and early in the morning.Keywords: unoprostone, intraocular pressure, diurnal variation, healthy voluntee