Moving towards successful exon-skipping therapy for Duchenne muscular dystrophy

17 May 2024 Articles ، Akinori Nakamura Exon skipping therapy for DMD ، Dystrophin restoration in Duchenne dystrophy ، Antisense oligonucleotide therapy ، Gene therapy for muscular dystrophy ، PMOs and 2’OMeAO for exon skipping ، Multi-exon skipping strategies ، Clinical trials for Duchenne dystrophy treatments

Summary

Duchenne muscular dystrophy (DMD) is a severe, X-linked disorder characterized by progressive muscle wasting due to mutations in the dystrophin gene. Exon-skipping therapy, utilizing antisense oligonucleotides (AOs), aims to bypass mutated exons, restoring the reading frame and enabling the production of functional dystrophin, thereby converting DMD to a milder Becker muscular dystrophy (BMD) phenotype.

1. Introduction

DMD is caused by mutations in the dystrophin gene, leading to the absence of dystrophin protein and resulting in muscle degeneration and necrosis.
Clinical symptoms include early-onset muscle weakness, loss of ambulation by early teens, and premature death due to respiratory or cardiac failure.
The dystrophin gene is located on the X chromosome and comprises 79 exons, with hotspot mutations often occurring between exons 3–8 and 45–55.

2. Exon-Skipping Therapy

AOs are designed to bind specific sequences of dystrophin pre-mRNA, leading to the exclusion of targeted exons during mRNA splicing.
Effective AOs include:
- 2′-O-methyl-phosphorothioate (2′OMeAO)
- Phosphorodiamidate morpholino oligomers (PMOs)
Exon skipping corrects the reading frame, producing a shorter but functional dystrophin protein akin to that seen in BMD.

3. Clinical Trials and FDA-Approved Drugs

Clinical trials with:
- Drisapersen (2′OMeAO)
- Eteplirsen (PMO) – FDA approved
- NS-065/NCNP-01 (Exon 53 skipping)
- SRP-4045 (Exon 45 skipping)
Exon-skipping targeting exon 51 can treat ~13% of DMD patients, while exon 53 skipping can treat ~10%.

4. Challenges and Future Prospects

Short half-life of PMOs requiring frequent administration.
Variable efficiency across tissues, with lower dystrophin induction in heart muscle.
Potential for multi-exon skipping (e.g., exons 45–55) to treat ~60% of DMD patients.

Conclusion

Exon-skipping therapy represents a promising genetic approach to treat DMD. However, advancements in AO chemistry, improved delivery methods, and thorough clinical evaluations based on large-cohort studies are essential to ensure its efficacy and success.