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Around 5–70% of cases of some genetic diseases are caused by mutations that introduce a premature ‘stop’ signal into the gene. When the cellular machinery that translates genetic information into proteins encounters a messenger RNA (mRNA) that has such a premature ‘stop’ signal (also known as a nonsense mutation), it stops translating the message and produces a truncated, non-functional protein. Researchers at the PTC Therapeutics Company in the US have developed a drug that could be a powerful treatment for diseases caused by nonsense mutations, by enabling the translational machinery to read through a premature stop signal and produce a stable, functional protein [Welch EM et al. (2007) Nature advance online publication doi:10.1038/nature05756 (abstract)].

The drug, PTC124, was selected from a high-throughput screen of about 800,000 low-molecular weight compounds, designed to detect candidates with nonsense-suppression activity. When tested on mouse models of the human genetic disease Duchenne muscular dystrophy (DMD), it enabled production of dystrophin protein at about 35% of normal levels and significantly reduced the muscle damage that is characteristic of this disease. The drug also appeared to work in cell cultures from human patients with DMD.

PTC124 has several important features that make it a promising therapeutic candidate: it can be administered orally; it appears so far to be safe and non-toxic; it is specific for nonsense mutations and does not affect normal translational termination; and it works only by allowing read-through of premature stop signals, and does not affect an important cellular mechanism that degrades abnormal mRNAs.

Comment: PTC124 could potentially be used to treat any genetic disease caused by a nonsense mutation, provided the drug could be administered before any irreversible damage had occurred. For example, about 13% of DMD cases, and 10% of cases of cystic fibrosis, are caused by nonsense mutations; nonsense mutations also feature in hundreds of other genetic diseases including beta-thalassaemia, Hurler syndrome and haemophilia. In most cases, lifelong daily treatment would be necessary.

Although the researchers report that clinical trials of PTC124 are underway, the drug still has many hurdles to clear before it can be used clinically in humans.