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Editors Selection IGR 11-3

Response

Comment by Lambiase 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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General comment

Evidence-based letters and criticisms to published articles represent a living forum for readers and allow advances in scientific knowledge, when they are unbiased by personal reasons or conflict of interests. Therefore, our reply will be based on scientific evidence, to avoid that some speculations and erroneous statements included in comments #1 and #2 cause confusion and misinterpretation of our findings.

Comment 1

Without taking into account the rhetorical question which cannot open any serious scientific discussion, the commentator simply demonstrates with his words that he took more time to make negative comments than to read carefully our PNAS paper and its references. In fact, the 'twenty years of work already demonstrating neuroprotection' finds in our paper the attention that it deserves, being cited in the second paragraph of the introduction, with related references 4 to 6. The concept of neuroprotection (using neurotrophins such as BDNF) being already considered in glaucoma is also widely discussed in the discussion of our manuscript: we urge the author of this comment to read in our paper for instance 'An approach that would vastly improve the treatment [...] involve neuroprotection with exogenous neurotrophic factors^6,27', or 'NGF acts on numerous levels to promote neural recovery [...] and or by induction of other growth factors, including BDNF^8,35-37'. The author of this comment should also read more carefully literature published by others, since he claims that NGF is weakly trophic for RGC, while there are several in vivo and in vitro published studies (also cited by the author of comment #2) demonstrating the opposite.

Regarding the methods, we once again urge the author of this comment to read our manuscript more carefully: both animals not treated with eye drops containing NGF and experiments performed in a masked fashion are clearly reported.

Lastly, while we hope that future studies will strengthen our results observed with H/E staining, we are amazed to learn that the author of comment #1, by simply looking at the pictures is able to give a more accurate count of RGC loss than what we did with H/E staining.

Comment 2

The comment of this author about 'neuroenhancement' is interesting and in line with our discussion, and allows a valid basis for further critical evaluation of our findings for the readers. We agree also, as clearly stated in the PNAS paper, that our clinical results are only preliminary and intended to stimulate a clinical trial.

 Regarding his/her 'frustrations' the author should be very careful before making such offensive statements without having realistic information on PNAS editorial policies: our manuscript was indeed peer-reviewed and underwent a revision before publication (we invite the author of comment #2 to contact PNAS editors for confirmation); in addition, the policy of PNAS clearly indicates in the first page when a paper is contributed by National Academy members; despite the large number of peer-reviewed publications of all the authors of this paper in journals such as Lancet, New England Journal of Medicine, Journal of Cell Biology (just to name a few), we never hoped to be called 'colleagues' of a Nobel Laureate, but still wish to be defined as 'researchers' rather than 'friends'. We are confident that knowing more about PNAS editorial policies, the author of this comment will publish an amendment to apologize to Prof. Levi-Montalcini and PNAS editors.

Comment 3,4,5,6

We are pleased to read that these authors found our publication interesting and fully agree with them on the need of a clinical trial to confirm our preliminary results in only three patients with advanced glaucoma.

As previously stated, we hope that the interest raised by our PNAS publication will trigger further studies to strengthen our histological and immunohistochemical findings that NGF actually rescues RGCs. Meanwhile, supporting our TUNEL and molecular data on apoptosis occurring in the chosen animal model of glaucoma, there are several reports already published and cited in our references.

Regarding pharmacokinetics, we also find the comments very useful to trigger further studies on retinal NGF eye drops bioavailability in large animals.

Regarding control groups in our study we wish to specify that: 1) the control group received vehicle drops four times daily; 2) No significant difference was observed between the animal groups in IOP values during the experiment (seven weeks).

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