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Editors Selection IGR 24-3

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Comment by Harry Quigley 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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This study reports the effect of topically administered NGF on the survival of retinal ganglion cells in a rat model of experimental glaucoma. NGF drops, prepared by the investigators, were administered four times daily from the time of glaucoma induction into the glaucomatous eye. NGF treatment reduced the degree of RGC loss by approximately 50% for the period of the study (duration: seven weeks). A small clinical study was appended to the paper, reporting an improvement in visual field sensitivity for patients receiving topically applied NGF. Improvements are suggested by the analysis of automated perimetry and from electrophysiological studies- the largest improvement being seen in the amplitude of the VEP for patients on treatment. Significantly, the improvement appears to continue following discontinuation of the drops.

While the paper is thought provoking and builds on a body of literature that supports a neuroprotective effect for Nerve Growth Factor eye drops, the data should be interpreted with caution

While the paper is thought provoking and builds on a body of literature that supports a neuroprotective effect for NGF, the data should be interpreted with caution. One of the principle weaknesses of the study is the lack of a true control group. The animals receiving NGF were handled four times daily during the study - this manipulation was not reported for the control group (which should have received vehicle drops four times daily). We also do not know if the IOP readings were matched for the treatment and control groups. These are important considerations for the study. On a technical point, the model is reported as the Morrison model - but this does not appear to be the case from Figure 1, in which the optic nerve has been proptosed during the saline injection - could this manipulation confound the degree of damage due to ocular hypertension? The Morrison model is critically dependent on closure of the episcleral vessels posterior to the site of injection using an occluding ring (the induction in IOP elevation is unlikely to occur without the ring and the risk of collateral retinal damage increases). A typographical error in the methods has obscured the details of the strength of the saline solution used. The characterization of the IOP increase is also limited - were the IOPs shown (Figure 2) for all experimental groups? A multivariate analysis in which the effects of IOP fluctuation and integral IOP were determined would be helpful in defining the magnitude of the effect of NGF treatment. Finally, the authors should be clear about the methods for the determination of RGC loss; they imply that counts were made of cells in the retinal ganglion cell layer. There is good evidence to support this as a method for the quantification of RGC loss (compared with retrograde labeling techniques) but they should refer to loss of cells in the retinal ganglion cell layer, rather than RGC loss.The number of patients included is too small to make a valid comment. Indeed it would be helpful if studies of this size were not reported in peer-reviewed publications, given the known variability in patients with advanced glaucoma. The editorial board of PNAS should be alerted to the risks of reporting such data given the propensity for patient groups to search the literature for promising treatments. In summary, novel therapies for the protection or even regeneration of damaged/dying retinal ganglion cells are to be welcomed. The present study requires further detailed analysis and repetition before we can fully evaluate the potential for topical NGF in the management of glaucoma.

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