Developments in Duchenne Muscular Dystrophy Care: Examining the Options

Duchenne muscular dystrophy (DMD) is the most common childhood-onset muscular dystrophy. Caused by mutations in the DMD gene, this genetic disorder leads to the absence or reduction of dystrophin, a key structural protein in muscle cells. As a result, patients experience progressive muscle degeneration, loss of ambulation, respiratory failure, and premature death.

Historically, corticosteroids have been the primary treatment option, but advancements in genetic therapies, including exon skipping, gene replacement, and gene editing, are transforming the therapeutic landscape for DMD. Here’s an overview of the benefits and challenges associated with these management strategies.

Corticosteroids

Corticosteroids, the current standard of care of DMD, have been the cornerstone of treatment due to their ability to reduce inflammation, slow disease progression, and improve quality of life. These medications have been shown to prolong ambulation and support pulmonary and cardiac function. However, long-term use is associated with side effects such as weight gain, osteoporosis, and growth retardation.

Dissociative steroids, a glucocorticoid alternative, is a way to provide anti-inflammatory benefits while minimizing the adverse effects typically associated with corticosteroid therapy. The recent FDA approval of a dissociative steroid has helped patients with DMD preserve muscle function with fewer side effects.

Exon-Skipping Therapy

Moving on to steroid alternatives, exon skipping is a genetic therapy that uses antisense oligonucleotides to restore the open reading frame of the DMD gene, allowing for the production of a shortened but functional dystrophin protein. Several exon-skipping therapies have been developed, each targeting specific exons to restore dystrophin production in different subsets of patients.

While this approach has shown promise in increasing dystrophin levels and modestly slowing disease progression, it does not fully restore normal dystrophin function and requires ongoing, frequent administration. Future research aims to enhance the effectiveness and expand the number of eligible patients for this therapy.

Micro-Dystrophin Gene Therapy

In the realm of gene therapy, a few transformative DMD treatment strategies have emerged. Since the DMD gene is too large to fit into traditional viral delivery systems, researchers have developed micro-dystrophin constructs—smaller but functional versions of dystrophin—that can be delivered using viral vectors.

Clinical trials have demonstrated significant dystrophin expression and functional improvements using adeno-associated virus vectors to deliver micro-dystrophin. This approach has recently received FDA approval for use in ambulatory and non-ambulatory individuals, marking an important step toward a long-term treatment for DMD.

However, despite its promise, challenges remain, including immune responses to viral vectors, variability in treatment response, and potential toxicity. Ongoing research aims to optimize delivery methods and expand patient eligibility.

Gene Editing with CRISPR

Finally, CRISPR-Cas9 gene editing offers a potential curative approach for DMD by directly correcting mutations in the DMD gene. Preclinical studies in animal models have demonstrated the ability to restore dystrophin expression and improve muscle function.

However, the first human clinical trial using CRISPR for DMD experienced complications, highlighting the need for further refinement before broader clinical application. Researchers are working to enhance safety, efficiency, and delivery mechanisms to maximize the benefits of gene editing for patients.

The Future of DMD Treatment

DMD remains a devastating and life-limiting disorder, but new therapies are providing potential for improved outcomes. Corticosteroids continue to play a role in disease management, while exon-skipping therapies offer mutation-specific treatment options. Gene therapy, particularly micro-dystrophin replacement, represents a major advancement, with clinical trials showing promising results. CRISPR gene editing holds potential for a one-time curative solution, though further research is needed to ensure its safety and effectiveness.

As these therapeutic strategies continue to evolve, a combination of approaches may provide better long-term management and quality of life for individuals with DMD.

References

Brenda Kohn, Daniel Mak. US FDA-approval of VAMOROLONE for Duchenne Muscular Dystrophy (DMD)*-a novel alternative steroid with unique properties. Pediatric Endocrine Society. Published February 21, 2024. Accessed February 6, 2025. https://pedsendo.org/new-meds-and-tech/us-fda-approval-of-vamorolone-for-duchenne-muscular-dystrophy-dmd-a-novel-alternative-steroid-with-unique-properties/

D’Ambrosio ES, Mendell JR. Evolving Therapeutic Options for the Treatment of Duchenne Muscular Dystrophy. Neurotherapeutics. 2023;20(4):1669-1681. doi:10.1007/s13311-023-01423-y.

FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy. U.S. Food and Drug Administration. Published June 20, 2024. Accessed February 6, 2025. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy