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Editors Selection IGR 11-1

Comments

Comment by Makoto Aihara on:

24490 Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma, Lambiasea A; Aloe L; Centofanti M et al., Proceedings of the National Academy of Sciences of the United States of America, 2009; 106: 13469-13474

See also comment(s) by Jeffrey Goldberg • Leonard A. Levin • James Morgan • Neville Osborne • Harry Quigley • Lambiase •

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Would you attempt to demonstrate neuroprotection by using three severely glaucomatous eyes, five total field tests without multiple baselines to avoid regression to the mean, and neither masking nor a placebo group? Lambiase et al. combined that with rat experiments, attempting to show beneficial effects of nerve growth factor (NGF) eye drops. The authors claim this may 'open therapeutic perspectives for glaucoma,' but they failed to cite twenty years of work already demonstrating neuroprotection in experimental glaucoma and other optic nerve injury models by neurotrophins (BDNF and CNTF). They ignore the fact that NGF is weakly trophic for retinal ganglion cells (RGC) in vivo and in vitro, compared to BNDF or CNTF.

Treatment of rats was also not masked, and no placebo eye drops were given, so treated rats were handled four times per day for seven weeks, while the glaucomatous controls were not, clearly a possible confounder. The episcleral hypertonic saline glaucoma model was used, but none of the results took into account the possibility of differences in IOP exposure between treated and glaucoma control animals - a factor which must be considered to rule out the chance that an apparent protective effect resulted from lower IOP. The method of counting cells in RGC layer (H/E stain) is not specific for RGCs, so their 40% loss is likely to mean that 80% of RGC were killed in seven weeks.

This report, stating that it shows 'long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity' for glaucoma is based on poorly controlled research in a tiny group of eyes

Half of the cells counted would be amacrines, but all those dying would be RGC, so RGC loss is twice the percentage reported. The rate of RGC death is dramatically higher than in many other publications, while the standard deviations (or standard errors, it isn't stated) are dramatically small. The figure showing TUNEL labeling is seriously flawed, showing nonspecific labeling of the entire nerve fiber layer instead of local label over nuclei of individual RGC.

We are all interested in finding neuroprotective treatments that slow progression of glaucoma. Neurotrophin delivery (CNTF) through capsules containing immortalized, genetically engineered human cells are presently in phase-3 trials for human retinitis pigmentosa. But, this report, stating that it shows 'long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity' for glaucoma is based on poorly controlled research in a tiny group of eyes.

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