Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy

Elizabeth Crabtree; Katy Uribe; Sara M. Smith; Darby Roberts; Jacklyn H. Salmon; Jacquelyn J. Bower; Liujiang Song; Prabhakar Bastola; Matthew L. Hirsch; Brian C. Gilger

doi:10.1371/journal.pone.0270972

Peer Review History

Original SubmissionNovember 26, 2021
10 Mar 2022 Decision Letter - Andrew W Taylor, Editor PONE-D-21-37491Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapyPLOS ONE Dear Dr. Crabtree, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. There are several critical issues raised by the reviews that include missing information in the methods and in the experimental approach. Please submit your revised manuscript by Apr 24 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Andrew W Taylor, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels. In your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. Email us at plosone@plos.org if you have any questions. 4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 5. Please upload a new copy of Figures 4 as the detail is not clear. Please follow the link for more information: " ext-link-type="uri" xlink:type="simple">https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/" https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors address the significant unmet need for an effective, local, non-corticosteroid treatment option for non-infection uveitis. The goal of the study is to use a rat model of uveitis to study feasibility of their gene therapy approach prior to use in equine recurrent uveitis (ERU). The authors test the ability of two doses of an AAV8 vector expressing IL-10 to prevent EAU in Lewis rats. They conclude that intravitreal injection of both low and high dose vectors significantly decreased ocular inflammation and retinal damage. The manuscript is well written. The intro and discussion are thorough, and figures are appropriate. There are a few experimental design concerns that limit the significance of the conclusions. Specifically, that the treatment effect is local, and that the treatment approach is sufficient to treat uveitis in the presence of an established anti-retinal T cell population. Despite these concerns, this is an interesting study. Experimental design: 1. Immunosuppression administered prior to or during the immunization phase of EAU can prevent development of the anti-ocular T cell population. • In this study, it would be important to show that the local treatment approach (administered prior to uveitis induction) did not prevent the development of the expected autoreactive T cells. Ultimately for this gene therapy approach to be effective it must function in the context of the anti-ocular effector T cell population. Currently that data could also be interpreted to mean that the treatment prevented the generation of the anti-ocular T cell population at the time of immunization. o Optional experiments would be to treat rats with IVT AAV8-IL-10 and then use adoptive transfer to generate EAU. Alternatively, T cell ELISPOT from immunized rats could be used to demonstrate the autoreactive T cells were present. 2. With the assumption that an autoreactive T cell population was generated as expected (see above concern), it is not clear that the beneficial effect of the gene therapy is local to the eye. The low dose treatment showed the same benefit as high dose treatment, but without similar evidence of local gene expression. An alternative hypothesis is that increased systemic IL-10 expression (in eye draining local lymph nodes or the spleen for example) could be responsible for the beneficial treatment effect. This could be addressed in the discussion and further mechanistic studies. Additional experiments to address this concern would be beyond the scope of this proof-of-concept study. Statistical question: • Was clinical score data (Figure 1) analyzed per eye or per animal? Please clarify. If per eye, there needs to be an adjustment to account for non-independence of eye level data, or score could be assigned per animal by averaging both eyes. Comment: Cell mediated killing of transduced cells is a concern for the safety and efficacy of gene therapy approaches. I was stuck by the appearance of the ciliary body in the high dose treatment group. There looks to have been considerable loss of CB tissue and thinning of the iris. Was this seen in multiple eyes, or is just this section abnormal? Reviewer #2: This manuscript reports intravitreal administration of an IL-10-AAV8 vector 7 days prior to inducing EAU in Lewis Rats, and the authors were able to detect IL-10 transcripts in ocular tissues and found a reduction in EAU and in the inflammatory cell infiltration in the IL-10-AAV8-treated EAU rats relative to BSS-injected EAU controls. They conclude this to be an effective therapy which should be considered for treating equine recurrent uveitis. Comments: 1. How many experimental replicates were performed in this study? It would appear from the text that only one experiment was carried out with 14 rats divided into three treatment groups. Due to the variability in EAU in rodent models, it is expected that any treatment effect be reproduced at least 3 times. Can the authors please clarify in the Results how many repeat experiments were carried out. 2. The use of the rat model in interesting as it is generally an acute form of ocular inflammation which eventually burns out over the course of a few weeks. Did the authors consider using a more recurrent form of EAU in mice? This might potentially be a more representative model with which to test this novel therapy. 3. Given that rat EAU is a very acute, and clinically severe form of uveitis, it is nevertheless impressive that a suppression of EAU was observed using both doses of vector. Did the authors consider administering the treatment 7 days AFTER inducing EAU? This is a commonly used approach to determine whether a treatment can down regulate an already established disease, and should be discussed in respect of the current study. 4. The histology images in Fig 3 are too faint in my version to easily detect the infiltrating cells, and should be taken at a higher resolution. The retinal layers appear relatively unaffected, but have become detached from the choroid. Is this an artefact of the fixation proceedure, or an effect of the EAU? 5. Whilst I agree that it is good to detect IL-10 in the ciliary body and iris, the blood-retinal barrier at the level of the retinal endothelial cells is also a key part of the barrier. It would be helpful if semi-quantitative data for the IL-10 PCR in each tissue was shown. Data in Fig 4 is difficult to understand, as there is no reference to IL-10, only vector cDNA. Whilst I appreciate that the safety issues were of huge concern, it is also important to know whether, at the larger concentration, IL-10 could in fact be detected within the retinal tissues. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0270972.r001
Revision 1
17 May 2022 Author Response Response to Reviewers, Manuscript: PONE-D-21-37491 Reviewer #1: The authors address the significant unmet need for an effective, local, non-corticosteroid treatment option for non-infection uveitis. The goal of the study is to use a rat model of uveitis to study feasibility of their gene therapy approach prior to use in equine recurrent uveitis (ERU). The authors test the ability of two doses of an AAV8 vector expressing IL-10 to prevent EAU in Lewis rats. They conclude that intravitreal injection of both low and high dose vectors significantly decreased ocular inflammation and retinal damage. The manuscript is well written. The intro and discussion are thorough, and figures are appropriate. There are a few experimental design concerns that limit the significance of the conclusions. Specifically, that the treatment effect is local, and that the treatment approach is sufficient to treat uveitis in the presence of an established anti-retinal T cell population. Despite these concerns, this is an interesting study. Response: Thank you for your comments Experimental design: 1. Immunosuppression administered prior to or during the immunization phase of EAU can prevent development of the anti-ocular T cell population. In this study, it would be important to show that the local treatment approach (administered prior to uveitis induction) did not prevent the development of the expected autoreactive T cells. Ultimately for this gene therapy approach to be effective it must function in the context of the anti-ocular effector T cell population. Currently that data could also be interpreted to mean that the treatment prevented the generation of the anti-ocular T cell population at the time of immunization. Optional experiments would be to treat rats with IVT AAV8-IL-10 and then use adoptive transfer to generate EAU. Alternatively, T cell ELISPOT from immunized rats could be used to demonstrate the autoreactive T cells were present. Response: These are excellent comments and we added discussion points around this. Although unproven, our hypothesis is that the intravitreal IL-10 gene transfer and expression is limited primarily to the eye, which is supported by the overall lack of peripheral transgene or viral genome expression. 2. With the assumption that an autoreactive T cell population was generated as expected (see above concern), it is not clear that the beneficial effect of the gene therapy is local to the eye. The low dose treatment showed the same benefit as high dose treatment, but without similar evidence of local gene expression. An alternative hypothesis is that increased systemic IL-10 expression (in eye draining local lymph nodes or the spleen for example) could be responsible for the beneficial treatment effect. This could be addressed in the discussion and further mechanistic studies. Additional experiments to address this concern would be beyond the scope of this proof-of-concept study. Response: Also excellent comments and we added discussion points. Our hypothesis is that there is a limit to effective transduction of ocular tissue and the low dose AAV-IL10 was sufficient to locally inhibit the inflammatory response. In this case, more AAV is not better. Statistical question: Was clinical score data (Figure 1) analyzed per eye or per animal? Please clarify. If per eye, there needs to be an adjustment to account for non-independence of eye level data, or score could be assigned per animal by averaging both eyes. Response: Thank you. We clarified the data analysis to indicated that scores were assigned to each individual rat, not eye, by providing an average score per animal. This eliminated the between-eye correlation. See changes in statistical analysis section and figure legends. Comment: Cell mediated killing of transduced cells is a concern for the safety and efficacy of gene therapy approaches. I was stuck by the appearance of the ciliary body in the high dose treatment group. There looks to have been considerable loss of CB tissue and thinning of the iris. Was this seen in multiple eyes, or is just this section abnormal? Response: We have re-done this histology figure with better representative images and labels. The changes observed in this section were interpreted to be processing and sectioning artifacts and not therapy related. A more representative image was provided. Reviewer #2: This manuscript reports intravitreal administration of an IL-10-AAV8 vector 7 days prior to inducing EAU in Lewis Rats, and the authors were able to detect IL-10 transcripts in ocular tissues and found a reduction in EAU and in the inflammatory cell infiltration in the IL-10-AAV8-treated EAU rats relative to BSS-injected EAU controls. They conclude this to be an effective therapy which should be considered for treating equine recurrent uveitis. Comments: 1. How many experimental replicates were performed in this study? It would appear from the text that only one experiment was carried out with 14 rats divided into three treatment groups. Due to the variability in EAU in rodent models, it is expected that any treatment effect be reproduced at least 3 times. Can the authors please clarify in the Results how many repeat experiments were carried out. Response: The rat EAU model is well established in our laboratory and results from these experiments are reasonably consistent (see PMID: 31882729). Based on these previous studies, we powered our study design to account for model induction variation. 2. The use of the rat model in interesting as it is generally an acute form of ocular inflammation which eventually burns out over the course of a few weeks. Did the authors consider using a more recurrent form of EAU in mice? This might potentially be a more representative model with which to test this novel therapy. Response: Yes, we did consider other models such as recurrent EAU models in mice. However, for initial proof of concept studies, we elected to use a larger animal, more consistent, model to evaluate response to intravitreal AAV therapy. 3. Given that rat EAU is a very acute, and clinically severe form of uveitis, it is nevertheless impressive that a suppression of EAU was observed using both doses of vector. Did the authors consider administering the treatment 7 days AFTER inducing EAU? This is a commonly used approach to determine whether a treatment can down regulate an already established disease, and should be discussed in respect of the current study. Response: Yes, we did consider a treatment arm instead of a preventative arm. However, because it generally take 3-7 days for transgene expression to occur after injection of AAV, we felt that we may miss the therapeutic effect with the short duration of the EAU in this model. In the next phases of this study, use of the viral vector in a more chronic model after development of uveitis is planned. We added discussion points on this subject in the discussion. 4. The histology images in Fig 3 are too faint in my version to easily detect the infiltrating cells, and should be taken at a higher resolution. The retinal layers appear relatively unaffected, but have become detached from the choroid. Is this an artefact of the fixation procedure, or an effect of the EAU? Response: We have re-done this histology figure with better representative images and labels. The changes observed were interpreted to be processing and sectioning artifacts and not therapy or EAU related. 5. Whilst I agree that it is good to detect IL-10 in the ciliary body and iris, the blood-retinal barrier at the level of the retinal endothelial cells is also a key part of the barrier. It would be helpful if semi-quantitative data for the IL-10 PCR in each tissue was shown. Data in Fig 4 is difficult to understand, as there is no reference to IL-10, only vector cDNA. Whilst I appreciate that the safety issues were of huge concern, it is also important to know whether, at the larger concentration, IL-10 could in fact be detected within the retinal tissues. Response: We apologize for the confusion – For these experiments, both RNA and DNA were isolated from the described ocular tissues. RNA was treated with DNAse and a first-strand cDNA synthesis kit was used to generate cDNA for each sample. Primers and a probe specific to the Equine-IL-10 sequence were used to amplify Equine-IL-10 transcripts using qPCR. Figure 4a depicts these results detecting transcripts specific to the equine form of IL-10 (i.e. vector cDNA in this case refers to the quantification of the equine IL-10 transcript isolated from each ocular compartment). The data presented in Figure 4b represents the qPCR results of the DNA isolated from each ocular tissue (both genomic DNA and vector DNA) using the same Equine-IL-10 specific primer/probe set and represents the biodistribution of the AAV-Equine-IL-10 vector. Thus, as shown in Fig. 4a, the Equine-IL-10 transcript was detected in the retinal tissue at the high dose. We have amended the text in the results section and modified the figure legends to enhance the clarity of these results. While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. Response: We uploaded and formatted our figure files to the PACE digital diagnostic tool. The submitted figures were those generated by PACE. Attachments Attachment Submitted filename: Response to Reviewers eqIL10 Final.docx https://doi.org/10.1371/journal.pone.0270972.r002
22 Jun 2022 Decision Letter - Andrew W Taylor, Editor Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy PONE-D-21-37491R1 Dear Dr. Gilger, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Andrew W Taylor, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have been very responsive to reviews. My concerns have been addressed. Statistical concerns have been clarified and new histology images addressed my concerns about a toxic effect of treatment. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Kathryn Pepple, MD, PhD ******** https://doi.org/10.1371/journal.pone.0270972.r003
Formally Accepted
2 Aug 2022 Acceptance Letter - Andrew W Taylor, Editor PONE-D-21-37491R1 Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy Dear Dr. Gilger: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Andrew W Taylor Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0270972.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .