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Editors Selection IGR 11-3

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Comment by Neville Osborne 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

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Translational research in elevated intraocular pressure (IOP) models of glaucoma is particularly difficult because of anatomical differences between animals and humans, the need for an experimental intervention to elevate the IOP (which is prone to artifact), and the long time-course of the disease in humans, unmatched in typically used experimental animals. The study of Lambiase and colleagues should therefore be appreciated in light of the tremendous difficulties in translating work with animals to humans. Some of the more salient are the following:

1.  It appears that their elevated IOP model in the rat had effects on cells besides the retinal ganglion cell (RGC). Figure 2, panel C depicts not only decreased numbers of cells in the ganglion cell layer, but also thinning of the inner plexiform layer, inner nuclear layer, and outer nuclear layer. The number of cells in the ganglion cell layer was even lower than 50% of control, which would only be seen if there were also death of displaced amacrine cells that make up 50% of that layer in the rat.
   The implication is that although the model used does cause loss of RGCs, it also causes panretinal damage, and thus does not precisely mimic the human disease.
2.  The NGF was delivered topically, which in the rat, likely causes significant absorption through paths other than transcorneal, and given the small size of the rat eye, probably resulted in high concentrations at the retina. Topical delivery in the human would be unlikely to produce equivalent levels. In point of fact, the concentrations used (200 micrograms/mL) are so high that it is possible that there were off-target effects beyond binding to the TrkA receptor.
3.  The bcl-2/bax ratio reflects levels in all of the cells of the retina, but theoretically it is what happens in the RGCs that is most relevant to glaucomatous optic neuropathy. The large effect of NGF on this ratio for mRNA and protein in glaucomatous retinas may not be very helpful for ascertaining RGC-specific cell rescue.
4.  The human studies were performed in only three subjects, and thus are too subject to variability. The visual fields need several baseline studies. Artifactual fields should be discarded.

Overall, it is exciting how this study has excited the popular media, and brought the possibility of neuroprotection to a greater audience. Hopefully, subsequent studies will continue to improve on the findings described.

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