It’s rare that a disease or disorder can be attributed to a single mutation in a gene let alone to a single gene but in certain cases such as in Cystic Fibrosis and Rett syndrome this is exactly what happens. If you were able to find the gene that was responsible for such a disease you might think that you were well on the way towards developing a treatment or cure, but this has proved not to be the case. The problem lies in the fact that the mutations that are often associated with disease usually lead to “silencing” of a vital protein, be it an enzyme or receptor, meaning that the protein is non-functional or is not expressed at all. Medicinal chemistry is only good at modulating (ie. inhibiting or activating) proteins that work normally so there is a fundamental problem in dealing with proteins that don’t work correctly or are not even present.
That is why a recent paper in the May 3rd issue of Nature caught my attention. In it researchers from PTC Therapeutics describe a small molecule PTC124 which is able to resuscitate a protein which contains a mutation that prevents it from being synthesized.
The gene in question is dystorphin which is involved in Duechenne muscular dystrophy and the mutation is a so-called ‘nonsense’ mutation which acts as a mRNA stop signal inhibiting the complete translation of the protein.
Earlier experience with the aminoglycoside Gentamycin showed that it was possible to use a small molecule to suppress the ‘stop’ signal on an mRNA leading to synthesis of the complete fully functional protein. Unfortunately, this compound showed poor in vivo efficacy and was associated with toxic side effects.
A screening effort led to the discovery of PTC124, a remarkably simple looking molecule that was more amenable to drug development. The compound effectively suppresses the stop mutation in cell culture and in mice expressing the mutation. It is currently in clinical trials and the FDA has granted it fast track designation as a potential treatment for Duechenne muscular dystrophy and/or cystic fibrosis.