Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy

17 September 2024 Articles ، Haluk Topaloglu Exon skipping trials in Duchenne muscular dystrophy ، FDA-approved exon skipping therapies for DMD ، Eteplirsen, Golodirsen, and Viltolarsen clinical trials ، AON-based therapies for dystrophin restoration ، Challenges in exon skipping therapy delivery ، Long-term effects of exon skipping in DMD ، New exon skipping drugs for Becker muscular dystrophy

1. Introduction

Duchenne Muscular Dystrophy (**DMD**) is a severe **genetic disorder** caused by **mutations in the dystrophin gene**, leading to **muscle degeneration** and **progressive weakness**. In recent years, **exon skipping therapy** has emerged as a promising **molecular treatment**, utilizing **antisense oligonucleotides (AONs)** to **restore the reading frame** of the dystrophin gene. This therapy aims to **convert the severe DMD phenotype** into a **milder Becker muscular dystrophy (BMD) form**.

2. FDA-Approved Exon Skipping Therapies

Eteplirsen (Exon 51) – The first exon-skipping drug approved by the FDA.
Golodirsen (Exon 53) – Another exon-skipping drug approved for specific DMD mutations.
Viltolarsen (Exon 53) – Approved alongside Golodirsen for exon 53 skipping.
Casimersen (Exon 45) – Recently approved for patients with exon 45 mutations.

3. Mechanism of Action

Exon skipping works by **using AONs to bind specific mRNA regions**, hiding the targeted exon from the **splicing machinery**, allowing the production of a **functional but shorter dystrophin protein**. Advances in **AON delivery** and **stability enhancement** have led to chemical modifications such as:

2′-O-methyl phosphorothioate (2OMePS) – Enhances AON stability and efficiency.
Phosphorodiamidate morpholino oligomers (PMOs) – Improves drug delivery to muscle cells.

4. Challenges and Limitations

**Low dystrophin restoration levels** – Current therapies only produce small amounts of functional dystrophin.
**Frequent intravenous infusions** – Most treatments require **weekly administration**, which is burdensome.
**Limited effect on heart function** – The impact of exon skipping on **cardiac muscle** remains unclear.
**High cost and accessibility issues** – These therapies remain expensive and are not widely available.

5. Future Directions

Despite these challenges, **ongoing research** is exploring **next-generation exon skipping therapies**, improving **AON efficiency**, and **developing multi-exon skipping approaches**. These advancements could enhance **treatment outcomes** and provide **better therapeutic options for DMD patients**.