What is the mechanism of Viltolarsen?

Viltolarsen is a medication designed to treat Duchenne muscular dystrophy (DMD), a severe type of muscular dystrophy characterized by rapid progression of muscle degeneration, leading to loss of ambulation and ultimately respiratory and cardiac failure. The primary cause of DMD lies in mutations in the DMD gene, which encodes the dystrophin protein. Dystrophin plays a crucial role in maintaining the integrity of muscle fibers. When this protein is absent or not functional, muscle fibers are damaged during contraction and relaxation, leading to progressive muscle weakness.

The mechanism of action of Viltolarsen centers around a genetic therapy approach known as exon skipping. Exon skipping aims to restore the production of a functional form of dystrophin, albeit a shorter version than the full-length protein, by “skipping” over the faulty part of the gene that contains a mutation.

Specifically, Viltolarsen is an antisense oligonucleotide (ASO). ASOs are short, synthetic strands of nucleic acids that are designed to bind to specific sequences of RNA. In the case of Viltolarsen, the ASO is targeted to exon 53 of the dystrophin pre-mRNA. This targeted binding causes the cellular machinery to skip over exon 53 during the splicing process of the precursor mRNA, effectively excluding it from the final mRNA transcript.

Skipping exon 53 can restore the reading frame of the dystrophin mRNA, meaning that the resulting protein, although shorter and partially functional, can be produced. This truncated version of dystrophin retains some of the functional domains necessary for muscle fiber integrity, thereby mitigating some of the symptoms associated with DMD.

The administration of Viltolarsen involves intravenous infusions, making it necessary for patients to receive regular treatments. Clinical studies have shown that Viltolarsen can increase dystrophin levels in muscle tissue, which is a promising indicator of its therapeutic potential. However, it is important to note that while Viltolarsen can improve muscle function and slow down disease progression, it is not a cure for DMD.

The development and approval of Viltolarsen represent a significant advancement in the treatment of DMD, particularly for patients with mutations amenable to exon 53 skipping. By directly addressing the genetic defect that causes DMD, Viltolarsen exemplifies the potential of targeted genetic therapies in managing genetic disorders.

In conclusion, Viltolarsen operates through the mechanism of exon skipping, targeting exon 53 of the dystrophin pre-mRNA to produce a partially functional dystrophin protein. This approach can improve muscle function and slow disease progression in patients with specific genetic mutations, offering a new avenue of hope for those affected by Duchenne muscular dystrophy.