Stop codon readthrough is an investigational therapy that enables cells to ignore the premature stop signal caused by nonsense mutations, and to continue producing a full protein. This type of mutation in the DMD gene is the cause of about 10–15% of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) cases.
What are stop codons?
Codons are sets of three nucleotides or building blocks of DNA. The same building blocks also make up the messenger RNA (mRNA), a temporary copy of a gene being expressed, which is used by the protein-making machinery of the cell. Each codon (except the stop codons) codes for a single amino acid (amino acids are building blocks of proteins).
Stop codons signal the end of protein synthesis. Sometimes, mutations called nonsense mutations occur and prematurely introduce a stop codon somewhere along the length of the gene. This can cause the cell’s machinery to abruptly stop producing the protein, resulting in a truncated or shortened form of the original protein, which is nonfunctional and usually degraded by the cell.
With stop codon readthrough, it is possible to trick the cell into ignoring this premature nonsense codon and continue with the synthesis of the protein. This therapy holds good promise for DMD and BMD patients whose condition results from having nonsense mutations in the DMD gene.
Stop codon readthrough therapies for DMD
Translarna (ataluren) is currently being investigated in DMD and BMD patients for reversing the effects of the nonsense mutation in the DMD gene. Although not yet approved in the U.S. Translarna, being developed by PTC Therapeutics, is approved for marketing across Europe and in the U.K. The use of Translarna in the U.S. is restricted to clinical trials only.
Gentamicin is an antibiotic that is used in the treatment of several bacterial infections and also is being investigated as a stop codon readthrough therapy for treating DMD. A study found that gentamicin was somewhat effective in increasing levels of dystrophin protein in muscles and reducing creatine kinase in the blood of DMD patients. (Creatine kinase is a marker of muscle damage). However, the study could not demonstrate a clear clinical effectiveness at the investigated dosage.
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