Therapeutic Strategy and Clinical Path of Facioscapulohumeral Muscular Dystrophy: Review of the Current Literature

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review focuses on the genetic basis and clinical progression of musculoskeletal dystrophy (FSHD), highlighting the misexpression of the DUX4 protein in skeletal muscle as a cause of the disease. It discusses the shift in therapeutic strategies from symptom relief to gene therapy, which offers hope for the future, although it remains in clinical trials. The review also assesses the current advantages and challenges of FSHD gene therapy and the obstacles encountered in its clinical application.

While it is apparent that the authors put a lot of work into the literature review, which includes current medical knowledge on the subject, a few things need to be improved to improve the article.

First and foremost, it would be useful to add drawings that would allow the reader to more easily read the article's contents. Another thing is the authors' comment about the limitations of this review. Adding information about what the authors think will be the directions in the future in this topic will also improve this article.

Author Response

Comments1:First and foremost, it would be useful to add drawings that would allow the reader to more easily read the article's contents.

Respose1:We are very grateful to you for pointing out this defect in this manuscript. This is indeed the deficiency of the manuscript. We have drawn and provided three pictures and a table to illustrate the problems discussed in this manuscript. (Figuer1, page2.  Figure2, page3.  Figure3, page5.  Table1, page6-7)

Comments2：Another thing is the authors' comment about the limitations of this review

Respose2:As you suggested that we need this part. After seriously thinking about the shortcomings of the manuscript. We added limitations in the 4th paragraph on page 10 of the manuscript.

Comments3：Adding information about what the authors think will be the directions in the future in this topic will also improve this article.

Respose3:By consulting more therapeutic strategies with FSHD, such as stem cell therapy or personalized therapy, and considering the feasibility of its future development, we have made a vision for the future of FSHD.( We added it to the 6th section: Conclusion and prospect: Lines 14-18 of the first paragraph, and the second and third paragraphs. (page10-11).

Thank you once again for taking the time to provide your insightful comments on this manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors While the article presents an intriguing and novel topic, it lacks sufficient depth and specificity in its content. The absence of visual aids, such as tables, pathways, schemes, figures, and forest plots, makes the paper less engaging and less scientifically rigorous, relying heavily on opinion rather than empirical evidence.

To enhance understanding of the pathological and physiological mechanisms of genes, the inclusion of a pathway diagram, key molecule images, and gene expression distribution would have been valuable. Unfortunately, the authors omitted these visual aids

4.3. Crispr The emergence of Crispr technology provides new possibilities for gene therapy. Is repeated in 3.3 and 4.3 The authors' general overview of CRISPR technology lacks specificity in relation to Facioscapulohumeral Muscular Dystrophy (FSHD). A more focused analysis would require exploring any existing CRISPR experiments that have targeted the DUX4 gene, a key player in FSHD pathogenesis and follow this idea until they are able to close it.

4.2. Oligonucleotide drugs Oligonucleotide therapies,

The authors' overview of oligonucleotide therapies for muscular dystrophy lacks specificity regarding FSHD. A more focused discussion would require exploring any available research or clinical trials examining the potential of oligonucleotide drugs to modulate DUX4 expression, a promising therapeutic strategy for FSHD

 

To enhance the readability and scientific rigor of the paper, the authors should incorporate diagrams, specific data, pathways, and other visual aids. Additionally, they should provide detailed information on what has been done, what should be done, and the potential outcomes for each therapeutic approach related to Facioscapulohumeral Muscular Dystrophy (FSHD).

Comments on the Quality of English Language

The writing could be improved

Author Response

Comments1:  It lacks sufficient depth and specificity in its content. The absence of visual aids, such as tables, pathways, schemes, figures, and forest plots, makes the paper less engaging and less scientifically rigorous, relying heavily on opinion rather than empirical evidence.

To enhance understanding of the pathological and physiological mechanisms of genes, the inclusion of a pathway diagram, key molecule images, and gene expression distribution would have been valuable. Unfortunately, the authors omitted these visual aids

Response1:  We are sorry for the absence of visual aids in this manuscript, which is one of the shortcomings of our manuscript. We have created and added diagrams illustrating the pathological mechanisms of FSHD, as well as pathways, genes, and key strategies related to FSHD gene therapy. (Figuer1, page2.  Figure2, page3.  Figure3, page5.)

Comments 2: 4.3. Crispr The emergence of Crispr technology provides new possibilities for gene therapy. Is repeated in 3.3 and 4.3

Response 2:   I'm sorry it was our negligence. We deleted the repeated sentences (4.3crispr.page10)

Comments 3: The authors' general overview of CRISPR technology lacks specificity in relation to Facioscapulohumeral Muscular Dystrophy (FSHD). A more focused analysis would require exploring any existing CRISPR experiments that have targeted the DUX4 gene, a key player in FSHD pathogenesis and follow this idea until they are able to close it.

Response 3:   Thank you very much for pointing out our lack in this part. We carefully reviewed and added more contents about CRISP specific targeting DUX4 in the treatment of FSHD, and focused on their achievements on DUX4, including in vivo and in vitro experiments. (Page 8, paragraph 3, lines 2-14 and page9, lines 3-9)

Comments 4: The authors' overview of oligonucleotide therapies for muscular dystrophy lacks specificity regarding FSHD. A more focused discussion would require exploring any available research or clinical trials examining the potential of oligonucleotide drugs to modulate DUX4 expression, a promising therapeutic strategy for FSHD.

Response 4:  In section 4.2 of our manuscript, we have added the research plan for ASOs targeting DUX4, detailing the development history and achievements of the currently most relevant ASO drugs, such as PMO, LNA, and other ASOs. (page9, lines 3-18). Meanwhile , we added the content of RNAi targeting DUX4 to illustrate their contribution and potential to FSHD treatment. (Page 8, paragraph 2, lines 5-12)

Comments 5:To enhance the readability and scientific rigor of the paper, the authors should incorporate diagrams, specific data, pathways, and other visual aids. Additionally, they should provide detailed information on what has been done, what should be done, and the potential outcomes for each therapeutic approach related to Facioscapulohumeral Muscular Dystrophy (FSHD). 

Response 5:  We believe that your suggestion to use visual charts to provide detailed information is very meaningful. We have summarized the various gene therapy methods described in this manuscript and made a table that details their treatment pathways, achievements, potential, and future challenges that need to be addressed. (Table1, page6-7)

Comments on the Quality of English Language

The writing could be improved.

Response: I'm sorry for the improper use of some English in our manuscript. We revised the problematic sentences in the article together with the professional English teacher and revised them to make our article as smooth as possible.

(Page 2, paragraph 2, lines 2-3 and 11-13

Page 3, paragraph 1, lines 1-2. Line 8-12, paragraph 2

Page 4, paragraph 2, lines 11-13. Lines 4-7 and 9-10, paragraph 3. Lines 2-5 , paragraph4 .lines 1-3 ,paragraph 5.

Page 7 Lines 1-2.

Page 9, paragraph 4, lines 10-13. Lines 7-8, paragraph 5. Paragraph 6, lines 2-4.

Page 10, paragraph 2, lines 10-15)

 

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authours, 

I have the pleasure of reviewing the work of Xie and colleagues. The paper shifts its focus to current advancements in treatment, particularly gene therapy. It highlights the transition from symptomatic relief to gene therapy approaches, which hold promise for future treatment but are still in the clinical trial phase. The paper evaluates the current state of gene therapy for FSHD, discussing both its advantages and disadvantages, as well as the challenges faced in its clinical application.

 

Unfortunetely I believe that this review lacks interesting approaches to differentiate it from more current and complete reviews on the theme as for example: PMID: 37404420, PMID: 35910413, PMID: 30361930 

Also there is a new Nature review that is outstanding: https://www.nature.com/articles/s41582-022-00762-2

Therefore I don't think this review adds much to the current literature. 

Author Response

Comments 1:Unfortunetely I believe that this review lacks interesting approaches to differentiate it from more current and complete reviews on the theme as for example: PMID: 37404420, PMID: 35910413, PMID: 30361930 

Response1:We carefully considered the concerns you raised and made revisions accordingly. We have added images and tables to visualize the various gene therapy methods for FSHD described in our manuscript, making it potentially more persuasive and less monotonous. (Figuer1, page2. Figure2, page3. Figure3, page5.  Table1, page6-7)

                    And we believe that the issue you raised is of profound significance to us. We have given it serious thought and greatly appreciate the references you provided. After thoroughly reviewing them（PMID: 37404420, PMID: 35910413, PMID: 30361930） , we reflected on the differences between our manuscript and these articles. We acknowledge that our manuscript does share similarities with the articles you provided, as both discuss gene therapy approaches targeting DUX4 and their current progress. However, we believe our manuscript focuses more on the clinical application of these approaches and the specific issues that need to be addressed. We have summarized the potential of these approaches and the future challenges in a table (Table1, page6-7)

Comments 2:Also there is a new Nature review that is outstanding: https://www.nature.com/articles/s41582-022-00762-2

Response 2:Thank you so much for providing this article, we carefully reviewed it and we find this article to be very meaningful, and the section of discussing the shift in treatment strategies for FSHD towards targeting DUX4 has been particularly helpful for us. We have referenced it in our manuscript. (Page 4, paragraph 5, lines 1-2)

Thank you again for taking the time to give useful comments on this manuscript. All changes are marked in red in the manuscript.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been revised according to my suggestions. The current form is much improved.

Author Response

Comments: The manuscript has been revised according to my suggestions. The current form is much improved.

Response: Thank you very much for your suggestions on this manuscript, which has helped us improve it.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper's visual impact has been significantly enhanced by the authors, who have skillfully employed tables and figures to improve clarity and comprehension and the authors have addressed most suggestions

Author Response

Comments: The paper's visual impact has been significantly enhanced by the authors, who have skillfully employed tables and figures to improve clarity and comprehension and the authors have addressed most suggestions

Response: Thank you again for the targeted contents and diagrams you suggested us to add to this manuscript to make this review more convincing.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

I appreciate the effort you have put into enhancing the quality of the work, including the addition of figures, tables, and additional literature. However, I still have some major and minor points that I believe need to be addressed to further improve the quality of the paper:

Major Point: The paper lacks a clear discussion of the methodology. Was this a literature review? If so, how were the papers selected? Are the points raised based on the experience of the authors' institution? I find that some context is missing. It might be helpful to include the methodology in the title, such as "Review of the Current Literature."

Minor Points:

• In the introduction, ensure proper spacing between "fascioscapulohumeral" and "(FSHD)."
• Correct the references in subitem 1.3.
• In Figure 3, the term "wnt" is underlined in red as if in a Word document.
• In Table 1, the first row of ASOs is missing reference numbers for Marsellier.

Author Response

Comments 1:  The paper lacks a clear discussion of the methodology. Was this a literature review? If so, how were the papers selected? 

Response1: We appreciate your feedback and have given it careful consideration. Indeed, our manuscript is a review, with methodology being a crucial part of the review. We conducted a comprehensive search of the databases for all current basic and clinical research related to gene therapy methods for FSHD, including ASOs, CRISPR, RNAi, and molecular drugs. We have summarized their progress and discussed the advantages and limitations of their future applications for patients. Therefore, we added methodology to the abstract of this manuscript. (Page 1, paragraph 1, lines 8-13)

Comments 2: Are the points raised based on the experience of the authors' institution? I find that some context is missing. It might be helpful to include the methodology in the title, such as "Review of the Current Literature."

Response2: The main direction of our research group is the gene therapy of DMD. DMD and FSHD belong to a kind of neuromuscular diseases caused by gene defects, and we are also faced with the problems (hepatotoxicity or immunogenic reaction) caused by exogenous injection of AAV virus during the research process. Therefore, through the analysis and discussion of the research in the database, we put forward the problems that must be overcome in the clinical application of gene therapy to FSHD.

          As you suggested, our manuscript was completed based on literature review. Therefore, it is correct for us to take your opinion and add “Review of the Current Literature” to our title. (Title, page1)

 

Comments 3: (1) In the introduction, ensure proper spacing between "fascioscapulohumeral" and "(FSHD)."

(2) Correct the references in subitem 1.3.

(3) In Figure 3, the term "wnt" is underlined in red as if in a Word document.

(4) In Table 1, the first row of ASOs is missing reference numbers for Marsellier.

Response3: I'm sorry for our negligence in this manuscript. We checked and revised it.

（1）(Page 1, paragraph 2, line1)

（2）We have corrected and supplemented the references in subitem 1.3 including references [11],[15],[16],[17]. (Page 2, paragraph 2, lines 4 and 13-15)

（3）We modified the Wnt in Figure 3 to make it consistent with that in the Word document (Figure3, page5).

（4）We added the missing references to the table. (Table1, page6).

 We would like to express our gratitude once again for your comments on this manuscript, which have greatly assisted us in improving it. The amendments are highlighted in blue in the revised manuscript.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

Accepted after the corrections