Some types of genetic disease, such as cystic fibrosis, may be beaten by overcoming the 鈥渘onsense鈥� mutations that cause them, researchers say. They have now identified a drug that appears to correct this kind of genetic defect in mice.
Nonsense mutations put premature 鈥渟top鈥� signals in the middle of genes, causing the cells鈥� protein-making machinery to stop too early. The non-functional proteins that result contribute to diseases such as cystic fibrosis and Duchenne muscular dystrophy. DMD, for example, is caused by a lack of the protein dystrophin, which helps maintain muscle fibre strength
Lee Sweeney at the University of Pennsylvania in the US and colleagues previously found that the antibiotic gentamicin could overcome the nonsense mutations responsible for around 15% of DMD cases. However, the drug proved too toxic, so Sweeney鈥檚 team screened 800,000 molecules to develop a drug called PTC124.
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Restored muscles
In a mouse model of DMD, PTC124 increased levels of functional dystrophin and restored muscle function.
Like gentamicin, PTC124 prevents ribosomes from recognising the 鈥渟top鈥� signals in messenger RNA (messenger RNA carries the blueprint for building a protein to the ribosomes, which are the cell鈥檚 protein-making factories).
Sweeney says the drug works by altering ribosomes to increase the frequency at which they can read through premature stop signals, allowing a therapeutic amount of functional protein to be made.
But unlike gentamicin, the drug does not affect normal stop signals, so it could be safer to use.
Safety check
Sweeney says that PTC124 appears to be safe in clinical trials in patients with DMD and cystic fibrosis.
Steve Hyde who works on gene therapies for cystic fibrosis at Oxford University says the drug will be useful, but limited by whether nonsense mutations are common in the particular patient鈥檚 DNA. For cystic fibrosis this varies with ethnicity.
鈥淚n the UK it is probably only about 5% of patients, but in Jewish populations it is much higher. If I was a cystic fibrosis patient in Israel I鈥檇 be quite excited,鈥� he says.
Journal reference: Nature, DOI: 10.1038/nature o5756
