PTC 124
PTC are a US biotech company that is working with PPMD through Project Catalyst to develop new drugs for Duchenne. Their lead candidate is a drug named PTC124. It was found that Gentamicin a known antibiotic was successful in reading through single point variations in the gene and helping to produce dystrophin. Unfortunately Gentamicin was toxic in the large doeses required for a therapuetic effect for Duchenne. PTC124 has been developed as an alternative to gentamicin..
From a report of the 2006 PPMD USA conference by Günter Scheuerbrandt:
Reading through premature stop codons.
Proteins are synthesized on ribosomes, complex structures consisting of three large RNAs with enzymatic activity, ribozymes, and about 80 different proteins. The information for the production of proteins is brought to the ribosomes as mRNAs. Inside the ribosomes, the new protein is assembled from its building blocks, 20 different amino acids. They are delivered to the assembly site by another kind of RNA, the transfer or tRNAs, which recognize the triplet codons of the mRNA one after the other.
When a normal stop codon arrives at the synthesis site, meaning that the protein is now ready to be completed, special proteins, release factors, enter the assembly site, bring the synthesis to a halt and release the completed new protein from the ribosome. About 10% to 15% of Duchenne boys have a point mutation in their dystrophin gene which changes an amino acid codon into one of the three stop codons, TGA, TAG and TAA. In the mRNA, these codons become UGA, UAG, and UAA and cause protein synthesis to shut down prematurely, before the new protein, in this case dystrophin, is fully assembled. The antibiotic gentamicin has been shown to interfere with the mRNA translation mechanism in the ribosomes so that it ignores such a premature stop codon, i.e. it reads through the stop codon. In animal models with a premature codon in the dystrophin mRNA, treatment with gentamicin has been shown to induce read-through and has partially restored production of full-length, functional dystrophin protein. However, gentamicin can be toxic and must be taken intravenously, so its long-term use as treatment for Duchenne muscular dystrophy is not practical. If an improved read-through technique can be developed as a therapy for Duchenne muscular dystrophy, the subset of patients with a nonsense mutation as the basis for the disease may be able to benefit from it.
Based on the pre-clinical studies in mice, the amount of new dystrophin made, will not cure the disease but may change it to a Becker-type dystrophy. As read-through does not occur at the gene level but during protein synthesis in the ribosomes, the treatment will have to be taken daily. To determine whether a Duchenne boy can be treated with a readthrough drug, it should be known that he has a point mutation in his dystrophin gene and that it has introduced one of the three different premature stop codons.
PTC 124: Langdon Miller, Chief Medical Officer of the company PTC Therapeutics in South Plainfield NJ
reported to the conference on the development and clinical testing of PTC124, a new chemical compound that is much more effective than gentamicin at reading through premature stop codons. Finding a therapy for Duchenne muscular dystrophy and cystic fibrosis, based on stop codon readthrough, are two of PTC's priorities. Several thousand chemical compounds were automatically tested for their ability to read-through premature stop codons in the mRNA for dystrophin or for the CFTR protein, the protein that is absent in cystic fibrosis. The structures of the most promising compounds were then changed through many chemical variations until one was obtained, PTC124, that is more efficient than gentamicin. In the Duchenne project, full-length dystrophin appeared in almost normal amounts in cell culture or in up to 25% of the muscle fibers of living mdx mice after oral application with a substantial rescue of their function and tissue structure. No read-through of normal stop codons was detected.
Toxicity studies in rats and dogs given high doses of the drug have generally not shown serious, acute side effects. This potential Duchenne drug is a powder that can be made into tablets and taken by mouth. In the first clinical testing of PTC124, two phase-I trials were performed in adult healthy volunteers. In these studies, the drug appeared safe and demonstrated few side effects.
Last year a phase-II trial of PTC124 in 15 cystic fibrosis patients has been performed. It showed that PTC124 is capable of partially restoring CFTR activity in these patients and did not show any serious adverse effects. At three clinical centers in the United States, a phase-II trial to test the effect of PTC124 in Duchenne patients is also now in progress. Twenty-two 5-12-year-old Duchenne boys with premature stop codons in the dystrophin gene participate in this study. The study was designed to last eight weeks. During the study, six boys were given a lower dose of PTC124 three times per day for four weeks followed by a four-week follow-up period without medication. When there were no adverse effects another group of 16 boys received a higher dose of PTC124 for four weeks, again followed by four weeks without the drug. To assess the outcome of the trial, muscle biopsies were performed before and after the treatment course to evaluate for the partial restoration of full-length dystrophin production.
Other chemical and functional tests were also done to quantitatively measure the therapeutic effect of PTC124 in Duchenne boys. These results will be available at the end of 2006. If they are as positive as expected from the preclinical development phase, and if the necessary permission is obtained from the regulatory agencies in Europe and the United States, a phase-III trial will possibly start next year or in 2008.