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Could you please give me some information about PTC-124. My children have the mutation F508/R553X. PTC-124 is according to my research only applicable for stopp-mutations. As a consequence also to the ones of my children? How far is the research on this field really?
Dear questioner,
thank you very much for the question about PTC-124 as a drug for the treatment of stopp-mutations.
PTC-124 is a substance that has been developed for the correction of early stopp-mutations at protein synthesis.
Our genetic information, which is defined in the DNA, is at first transcribed by the cell into the messenger substance mRNA. After that, the messenger substance is transported to the ribosomes. The sequence of aminoacids defined in the matrix, is then translated into protein at the ribosome. Start and end are defined via the start- and stopp-codon.
In case of the illness-causing stopp-mutations, the affected gene contains an early stopp-codon.
PTC-124 arranges, that at the ribosome such an early stopp-codon is ignored. In february 2008 researchers from the well-known journal PNAS reported, that PTC-124 indeed partially corrected the mutation G542X and greater amounts of fuctioning CFTR protein have been produced in CF mice, carrying the stopp- mutation G542X in the CFTR gene.
In the preclinical study of PTC-124 no severe side-effects have been observed in healthy humans.
In the USA, France and Israel PTC-124 is at the moment clinically tested in phase II studies with CF patients. According to first results, the impaired chloride-conductance at the airways in CF can be indeed partially corrected in CF patients carrying stopp-mutations in the CFTR gene.
The extent of the correction however, is dependent on the amount of CFTR messenger, the CFTR mRNA. In the nucleus of the cell there is an internal quality control, if an mRNA with an early stopp-codon had been produced. Some mutations, such as R1162X, are not recognized by the quality control and are therefore transported in large amounts to the ribosome. Such a mutation can therefore be corrected effectively by PTC-124 at the ribosome.
Other stopp-mutations in the CFTR gene, such as R553X however, are recognized by the quality control of the nucleus and are destroyed again right in the nucleus. Only very small amounts of R553X CFTR mRNA reach the ribosome. Therefore only few mRNA molecules can serve as a matrix, which can be corrected by PTC-124.
In addition, a recognizing signal for the correct synthesis of CFTR mRNA is destroyed by the mutation R553X. The CFTR gene is consisting of 27 coding segments, the exons, which are coding for the CFTR protein, and of intermittend non-coding segments, the so-called introns. During the synthesis of mRNA, the introns have to be cut out and the exons have to be connected correctly. Unfortunately, the mutation R553X leads to the absence of exon 11 in most CFTR mRNA molecules. Such a defect of the mRNA matrix can not be corrected by PTC-124.

1. PTC-124 is a promising substance for the correction of stopp-mutations.
2. The extent of the correction of an mRNA with an early stopp-codon depends on the assemblence of all exons into the mRNA and on the amount of mRNA messenger overlooked from the quality control in the nucleus and being transported to the ribosome.
3. The mutation R553X in the CFTR gene is recognized very efficiently by the quality control of the nucleus and is destroyed again right after synthesis. The mutation R553X destroys a recognizing signal for the assemblance of exon 11 into CFTR mRNA.
4. Stopp-mutations can influence the synthesis and lifespan of mRNA and protein.
5. PTC-124 is correcting the mistake of the stopp-mutation during reading of the mRNA matrix at the ribosome. Synthesis and lifespan of the mRNA are not influenced by PTC-124.
6. Animal experiments with CF mice and first clinical studies have demonstrated, that the basic defect in CF patients with stopp-mutations can be partially corrected with PTC-124. The success will be different for each stopp-mutation (see above). At the moment, no prognosis can be made yet about the chances of success for the treatment of R553X with PTC-124.

Dr. Burkhard Tümmler,
medical college Hannover, Germany