Exon 51 skipping therapy is a targeted genetic treatment for specific mutations in the dystrophin gene. It aims to restore the body’s ability to produce a functional, though shortened, version of the dystrophin protein.
Understanding Exon Skipping
Understanding exon skipping involves basic genetic concepts. Genes contain segments called exons and introns. Exons are coding regions for proteins, while introns are non-coding regions. During gene expression, the entire gene is transcribed into precursor messenger RNA (pre-mRNA).
Before protein production, introns are removed from pre-mRNA through splicing, forming mature messenger RNA (mRNA). This mRNA carries instructions to the cell’s protein-making machinery. Exon skipping manipulates this natural splicing, instructing the cellular machinery to “skip over” a specific faulty exon during RNA processing. This allows remaining exons to join, restoring the genetic “reading frame” and enabling production of a modified, functional protein.
Mechanism of Exon 51 Skipping Therapy
Exon 51 skipping therapy specifically works by using small synthetic molecules called antisense oligonucleotides (AONs). These AONs are designed to precisely bind to a specific sequence on the pre-mRNA molecule, effectively masking exon 51. This masking prevents the cellular splicing machinery from recognizing and including exon 51 in the mature mRNA transcript.
By skipping exon 51, the downstream exons can be joined together in a new combination. This rejoining restores the “reading frame” of the gene, which is like ensuring that the genetic instructions are read in the correct three-nucleotide groupings. When the reading frame is restored, even though exon 51 is missing, the cell can produce a truncated, or shorter, but still functional dystrophin protein. This modified protein can then help to maintain muscle integrity and function.
Conditions Treated
Exon 51 skipping therapy primarily targets Duchenne Muscular Dystrophy (DMD). DMD is a severe genetic disorder characterized by progressive muscle degeneration and weakness, caused by mutations in the dystrophin gene. These mutations often involve deletions of one or more exons within the dystrophin gene.
When these deletions occur, they frequently disrupt the gene’s reading frame, preventing the production of any functional dystrophin protein. Exon 51 skipping therapy is applicable to a specific subset of DMD patients—approximately 13% to 15%—whose dystrophin gene mutations can be corrected by skipping exon 51 to restore the reading frame. For example, patients with deletions of exons 48-50 or exon 52 are amenable to exon 51 skipping. This approach helps to produce a shortened, yet functional, dystrophin protein, which can help alleviate some of the disease symptoms.
Therapeutic Effectiveness and Practical Considerations
Exon 51 skipping therapy, such as Exondys 51 (eteplirsen), is administered weekly via intravenous infusion. Clinical studies have shown that this therapy can increase dystrophin levels in skeletal muscle in some patients, with an average increase of 2.8 times the baseline level after 48 weeks of treatment in one study of 12 boys. While this increase is still much lower than in individuals without DMD, it aims to slow disease progression and improve motor function.
Patients receiving this therapy may experience a range of side effects. Commonly reported adverse reactions in studies involving 163 patients include headache, cough, rash, and vomiting, with these occurring in over 10% of the study population. Hypersensitivity reactions, such as wheezing, chest pain, rapid heart rate, and hives, have also been reported during infusions. Patient selection for this therapy involves genetic testing to confirm a mutation in the dystrophin gene that is amenable to exon 51 skipping. The treatment is ongoing, requiring regular infusions to maintain the therapeutic effect.