From the journal RSC Chemical Biology Peer review history

06-Jun-2021

Dear Dr Khanna:

Manuscript ID: CB-REV-05-2021-000110
TITLE: Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.

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I look forward to receiving your revised manuscript.

Yours sincerely,

Cai-Guang Yang, Ph.D.
Associate Editor/RSC Chemical Biology
Professor/Shanghai Institute of Materia Medica, CAS
Phone: +86-021-50806029
Email: yangcg@simm.ac.cn

************

Reviewer 1

An interesting, comprehensive, and important review. This manuscript introduces and compares various kinds of novel therapeutic strategies, including the uses of antibodies, peptides and small molecules, that enhance pathological TDP-43 degradation and/or eliminate TDP-43 aggregates in TDP-43-related neuropathies. The authors also used figures to illustrate the structures of these candidates and their targeting sequences on TDP-43. Overall, the manuscript is well written and provides detailed information of different aspects of ways to mitigate the deleterious TDP-43 aggregates.

Several comments/ suggestions for revision by the authors:
(1) Some spelling errors of TDP-43 should be corrected;
(2) A table listing the research models and the outcome of uses of different drug candidates would help the readers;
(3) Some discussions on the current difficulties (such as delivery through the blood brain barriers) encounted in therapy of neurodegenerative diseases using antibodies or small molecule compounds and citations of the relevant literature, eg. Pardridge, M. (2020) and Cavaco, N. et al. (2020), would also strengthen the value of this review.

Reviewer 2

In this work, Liberty et al. have reviewed the possibility of targeting TDP-43 using small molecules, mostly focusing on antibodies and other small molecules. The work is generally well written and has the novelty of focusing on how this search could be aided by focusing on structural characteristics of TDP-43. This is not an issue that has often been examined in the context of TDP-43 and therefore the considerations made in this review will certainly of interest to the field. A few minor additions/clarifications should be considered by the authors.

a) Very recently, two new reviews on small molecule targeting of TDP-43 have been appeared in the literature and might be eventually mentioned/discussed in the work to provide readers with additional reference work on this topic that is clearly of high current interest (Br J Pharmacol. 2021 Mar;178(6):1298-1315 and Br J Pharmacol. 2021 178(6), pp. 1253-1256).

b) In the manuscript, the authors have well described the process of using TDP-43 structural information and use it to design new drugs in their lab and also in others. Regarding this issue, it would be of interest to readers how the application of computer-based approaches could help to predict additional TDP-43 targets. For example, have they thought of performing some preliminary exercises using computational platforms such as Schrödinger SiteMap to predict potential “druggable” sites in the TDP-43 domains, based on the limited structural information already available?. Even without extensive preliminary analyses, the authors might add a paragraph discussing how bioinformatics could help in this search.

c) Finally, taking in consideration the focus of this review on structural aspects of TDP-43 it would be good if the authors could write a short paragraph with regards to the Cryo-EM approaches that have been recently provided breakthrough insight in other pathological aggregates such as those present in Tau and alpha-synuclein fibrils/filaments. Although for the moment this approach with TDP-43 has only been used for filaments assembled in vitro and not on patient brains, it is very likely that this structural approach will provide in the future the mean to design small molecules which might specifically target these structures.

Referee: 1

Comments to the Author
An interesting, comprehensive, and important review. This manuscript introduces and compares various kinds of novel therapeutic strategies, including the uses of antibodies, peptides and small molecules, that enhance pathological TDP-43 degradation and/or eliminate TDP-43 aggregates in TDP-43-related neuropathies. The authors also used figures to illustrate the structures of these candidates and their targeting sequences on TDP-43. Overall, the manuscript is well written and provides detailed information of different aspects of ways to mitigate the deleterious TDP-43 aggregates.

We thank the reviewer and appreciate the comments.

Several comments/ suggestions for revision by the authors:
(1) Some spelling errors of TDP-43 should be corrected;
We apologize for the mistakes, we have gone through the manuscript and fixed them.

(2) A table listing the research models and the outcome of uses of different drug candidates would help the readers;
We thank the reviewer for this suggestion, we have added a table to describe each drug candidate and their outcome in various models.

(3) Some discussions on the current difficulties (such as delivery through the blood brain barriers) encountered in therapy of neurodegenerative diseases using antibodies or small molecule compounds and citations of the relevant literature, eg. Pardridge, M. (2020) and Cavaco, N. et al. (2020), would also strengthen the value of this review.
Thank you for this suggestion. We have added the following to our manuscript:
“Given the challenges consistently faced in neurodegenerative disease drug development, there needs to be extreme care in choosing appropriate: (i) animal models, potentially in combination with patient-derived stem cells, to translate specific disease hallmarks being targeted, (ii) formulation, delivery route and ability to eventually cross the blood-brain barrier by the drug candidates and (iii) better clinical trial design, should all be addressed as soon as possible for optimal and successful development of therapeutic candidates.”

Referee: 2

Comments to the Author
In this work, Liberty et al. have reviewed the possibility of targeting TDP-43 using small molecules, mostly focusing on antibodies and other small molecules. The work is generally well written and has the novelty of focusing on how this search could be aided by focusing on structural characteristics of TDP-43. This is not an issue that has often been examined in the context of TDP-43 and therefore the considerations made in this review will certainly be of interest to the field. A few minor additions/clarifications should be considered by the authors.

We thank the reviewer and appreciate the comments.

a) Very recently, two new reviews on small molecule targeting of TDP-43 have been appeared in the literature and might be eventually mentioned/discussed in the work to provide readers with additional reference work on this topic that is clearly of high current interest (Br J Pharmacol. 2021 Mar;178(6):1298-1315 and Br J Pharmacol. 2021 178(6), pp. 1253-1256).
We have added those references to the manuscript for the reader to refer to, but those strategies are not targeting TDP-43 directly, they are mitigating TDP-43 toxicity.

b) In the manuscript, the authors have well described the process of using TDP-43 structural information and use it to design new drugs in their lab and also in others. Regarding this issue, it would be of interest to readers how the application of computer-based approaches could help to predict additional TDP-43 targets. For example, have they thought of performing some preliminary exercises using computational platforms such as Schrödinger SiteMap to predict potential “druggable” sites in the TDP-43 domains, based on the limited structural information already available?. Even without extensive preliminary analyses, the authors might add a paragraph discussing how bioinformatics could help in this search.
We have performed Sitemap analysis on the N-terminal domain of TDP-43 as well as on the RRM1 in our papers (Francois-Moutal et al., 2019 and Mollasalehi et al., 2020). We are currently working on analyzing the other structures available in the PDB, notably on the CTD, but we feel this is out of the scope of this review.

c) Finally, taking in consideration the focus of this review on structural aspects of TDP-43 it would be good if the authors could write a short paragraph with regards to the Cryo-EM approaches that have been recently provided breakthrough insight in other pathological aggregates such as those present in Tau and alpha-synuclein fibrils/filaments. Although for the moment this approach with TDP-43 has only been used for filaments assembled in vitro and not on patient brains, it is very likely that this structural approach will provide in the future the mean to design small molecules which might specifically target these structures.
We thank the reviewer for this suggestion. We have added a couple of sentences in the discussion about the recent efforts by the Eisenberg group.

18-Jun-2021

Dear Dr Khanna:

Manuscript ID: CB-REV-05-2021-000110.R1
TITLE: Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape

Thank you for submitting your revised manuscript to RSC Chemical Biology. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below.

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With best wishes,

Cai-Guang Yang, Ph.D.
Associate Editor/RSC Chemical Biology
Professor/Shanghai Institute of Materia Medica, CAS
Phone: +86-021-50806029
Email: yangcg@simm.ac.cn

Reviewer 2

Authors have answered well the minor improvements suggest by reviewers