Bypassing mutations in genetic disorders 17/08/07. By the Wellcome Trust A new drug bypasses mutations found in diseases such as muscular dystrophy and cystic fibrosis.

As scientists have identified the genes damaged in a number of human diseases, attention has focused on the possibility of repairing or replacing the defective copies. But a publication in 'Nature' suggests that there may be an easier way: a drug that causes cells to skip past the harmful mutation.

Some human genetic diseases, including cases of cystic fibrosis and muscular dystrophy, are caused by what are called 'nonsense mutations'. These mutations change a gene so that one of the codes that normally signal the end of a protein appears somewhere in the middle of the gene, producing a truncated, non-functional protein. In recent years, it's become clear that cells use a different system to stop proteins at nonsense mutations from the one that stops them at the end of the protein.

A research team tested over 800 000 chemicals for their ability to allow cells to skip past nonsense mutations without interfering with the normal ends of proteins. Variations were created for those that worked, and the effectiveness and toxicity of these drugs were tested further. In the end, one drug survived the rigorous screening process, a chemical called PTC124.

PTC124 was then given to a mouse strain that develops muscular dystrophy. The drug restored production of the dystrophin protein and greatly reduced muscle damage, all without toxic side-effects. Because of this success, clinical trials of PTC124 in human patients have been started.

References

Welch EM et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007;447(7140):87-91. Abstract