Current and Emerging Therapeutic Strategies for the Treatment of Duchenne Muscular Dystrophy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a timely and generally well-structured narrative review covering mutation-agnostic and mutation-specific therapies for DMD. The manuscript demonstrates good breadth and includes recent developments (e.g., vamorolone, Elevidys, gene editing platforms). However, the paper currently reads more as a descriptive summary than a critical synthesis. Several areas require strengthening in rigor, balance, clarity, and organization before publication.

 

Major Revisions

1. The manuscript largely summarizes studies without critically evaluating evidence quality, trial limitations, or controversies. For example: exon skipping discussion mentions modest dystrophin levels but lacks deep analysis of clinical relevance; gene therapy section reports “trends toward stabilization” without discussing failed endpoints or debate in the field; safety concerns (e.g., deaths after Elevidys) are mentioned but not critically contextualized.

Authors should compare efficacy across modalities with quantitative benchmarks where possible, discuss strength of evidence (phase, sample size, endpoints), explicitly address controversies (e.g., surrogate endpoints vs. functional benefit), add a short critical summary at the end of each major section.

2. Therapies are presented sequentially rather than comparatively, making it difficult to understand relative value. Clinicians and researchers need prioritization and positioning of therapies. Authors should add a summary table comparing mechanism, mutation coverage, durability, regulatory status and key limitations. Also include a figure showing where each therapy acts along the disease pathway and expand discussion on combination therapy strategies.

3. Certain passages appear promotional rather than balanced. Statements like “represents a compelling… strategy” and “growing confidence in its benefit-risk profile.” Should be avoided. Authors should use more neutral scientific tone and explicitly discuss delivery barriers, manufacturing challenges, cost and access issues as well as regulatory uncertainty. Balance preclinical promise with clinical reality.

4. Section numbering and hierarchy are inconsistent and sometimes confusing. Clearly separate: Mutation-agnostic; Mutation-specific. Rebalance section lengths. Add brief transition paragraphs between major sections.

5. The review underemphasizes clinically meaningful outcomes. Authors should add subsection on outcome measures in DMD trials, discuss biomarker vs functional endpoint controversy, address payer and access considerations for high-cost gene therapies.

6. Some strong claims lack sufficient citation depth or nuance. Ensure each major claim is supported by high-quality references. Where evidence is mixed, explicitly say so. Prefer recent systematic reviews/meta-analyses when available.

7. The manuscript would benefit from visual synthesis. Authors should add therapeutic landscape schematic, mechanism diagrams, comparison table (high priority), timeline of approvals.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The paper “Current and Emerging Therapeutic Strategies for the Treatment of Duchenne Muscular Dystrophy” presents a comprehensive review of therapies for DMD. It highlights both mutation-dependent and mutation-independent strategies. Overall, this review could be of interest to Readers, however, some issues related to its structure, composition and content should be addressed.

1. My primary concern regards the use or rather the absence of figures. The paper would benefit from the inclusion of figures or tables that summarize the information presented in the text. Incorporating schematic diagrams or summary tables would enhance clarity and help readers navigate the data more effectively.
2. The formatting of the review requires correction as the division into chapters is currently unclear. The paper is organized into three main chapters:
   1. Introduction
   2. Mutation-Agnostic Strategies
   3. Discussion: Emerging Directions and Future Outlook

Chapter 2 contains 17 subchapters, but these should be reorganized into more specific chapters. For example:

• Subchapter 2.4 should be a separate chapter.
• Subchapters 2.7 and 2.8 should be merged under 2.6 or reorganized according to content hierarchy.

Specific Comments:

Lines 35–36: “Due in part to the large size of the DMD gene (~2.5 Mb) it is the most common muscular dystrophy worldwide, with an estimated incidence rate of 1 in 3,800–6,300 live male births.”

It is generally correct but slightly simplified. It is recommended to mention that, because of the large gene size, the DMD gene has a high spontaneous mutation rate, which contributes to the relatively high prevalence of DMD among monogenic disorders.

Chapter 2.2, Corticosteroids:
It is known that prednisone has dual activity as both a glucocorticoid receptor and mineralocorticoid receptor agonist, which may limit its use in some patients. This important point is not mentioned and should be added.

Lines 227–228: “Despite these breakthrough therapies, several challenges limit the overall impact of this novel genetic technology.”

The technology is not novel, as antisense oligonucleotides (ASOs) were first conceptualized in basic research in the late 1970s. The first clinical ASO therapy, fomivirsen, entered the clinic and received FDA approval in 1998, followed by the approval of eteplirsen in 2016. This historical context should be reflected in the text.

Lines 261–271 (2.7 Delandistrogene Moxeparvovec, Elevidys, Sarepta Therapeutics):
“In June 2024, the indications for Elevidys were expanded to include a broader age range (4 and older) and ambulatory status (non-ambulatory) range, reflecting growing confidence in its benefit-risk profile.”

However, subsequent safety findings in 2025 led to label revisions that now limit Elevidys use to ambulatory patients 4 years and older only, removing the non-ambulatory indication due to reports of serious liver injury in non-ambulatory patients. This important update must be clearly indicated. (https://www.fda.gov/news-events/press-announcements/fda-approves-new-safety-warning-and-revised-indication-limits-use-elevidys-following-reports-fatal?utm_source=chatgpt.com

This has to be clearly indicated.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors have made all recomended changes, significantly improving the manuscript.