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Editors Selection IGR 15-1

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Comment by Jeffrey Goldberg on:

56225 Glucose-induced temporary visual recovery in primary open-angle glaucoma: a double-blind, randomized study, Casson RJ; Han G; Ebneter A et al., Ophthalmology, 2014; 121: 1203-1211

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In a series of animal models of optic neuropathies including glaucoma and retinal ischemia models, Casson and colleagues have demonstrated a neuroprotective effect of exogenously supplying glucose, presumably supporting energy-deprived retinal ganglion cells in these disease models. Other studies examining other aspects of energy and metabolic balance have also supported the premise that retinal ganglion cells may perform better if given a 'metabolic booster shot', for example by increasing oxygen tension. Now Casson and colleagues take this research a step forward into the clinic.

In an initial phase on patients about to undergo vitreoretinal surgery they applied a 50% glucose topical solution every five minutes for one hour and found an increase in vitreal glucose in pseudophakic, but not phakic patients.

Using these data to select only pseudophakic POAG patients with moderate to severe optic neuropathy (average MD was -12.1), patients were randomized to a masked crossover design trial in an initial study of 50% glucose against 0.9% saline drops, and then a follow-up study of 50% glucose against equi-osmolar 8% saline. In both studies the investigators found an improvement in central contrast sensitivity and logMAR visual acuity during the 50% glucose treatment phases, when averaged across participants. Not all participants responded favorably to topical glucose, but the overall results are nevertheless impressive.

Strengths of the study included strong study design with statements of pre-selected endpoints and a rationale for each. A particular highlight is the investigators' willingness to take on a first-in-human trial of this sort, particularly as pre-clinical research has generated many candidate approaches for neuro-enhancement but few that have been translated to human testing.

Many candidate approaches for neuro-enhancement but few that have been translated to human testing

Limitations of the study were few and were mainly questions that can be addressed in follow-on research. One such question is whether there is any specificity to POAG patients, or would such enhancement be seen in normal subjects. In some ways this is irrelevant as an enhancement for POAG patients that also enhances visual function of non-glaucoma patients is still a significant step forward for the field as specificity to POAG is not a prerequisite for treatment. Although the investigators selected only pseudophakic patients based on the penetration of glucose into the vitreous, a topical application may reach retinal ganglion cells or the optic nerve without a significant elevation of vitreal levels in phakic patients, and given the significant fraction of phakic glaucoma patients, it would clearly be worth looking for an effect on function in this population.

Finally, the duration of effect and its implications for dosing should be assessed in future pilot studies, plausibly in preparation for larger, longer term multicenter trials that could assess long term safety, durability of enhancement, and neuroprotection. This latter point will be particularly interesting as could improving bioenergetics through exogenous glucose supply protect retinal ganglion cells from decline over the long term, in addition to promoting short-term neuro-enhancement? It is an exciting premise for patients to consider the possibility of offering an inexpensive topical therapy that could enhance function and perhaps provide protection against visual decline.

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