PTC124: Treatment for Genetic Diseases of Nonsense Mutations

DNA (Deoxyiribonucleic acid - chemicals inside the nucleus of a cell, carries the genetic instructions or hereditary traits making living organisms.) contains information on how to build proteins. Proteins do the work of the cell (structural and functional unit of all living organisms). Cell functions determine which proteins are built. For example: Information on how to build hemoglobin (a protein that carries oxygen) carried in DNA. Sickle - cell anemia occurs when incorrect DNA information leads to incorrect hemoglobin. Amino acids are the basis by which sub -- units of proteins are formed. Each protein formed by a chain of amino acids linked together through peptide bonds.

Many inherited diseases are linked to a nonsense DNA mutation (Caused copying errors in the genetic material during cell division (process by which cells divide into two cells), exposure due to ultraviolet, radiation, chemicals or viruses) inactivate gene function. Nonsense mutation instead of substituting one amino acid for another, altered DNA sequence prematurely signals the cell to stop building a protein. A shortened protein (mutation) may function improperly or not at all, an inherited birth defect. Nonsense mutations inactive gene function cause five to seventy percent of most inherited diseases, as such fibrosis (10% -- cystic fibrosis an inherited disease of mucus and sweat glands. Affects mostly the lungs, pancreas, liver, intestines, sinuses, and sex organs.), and Hurler's syndrome or Gargoylism (70% - Lack the enzyme needed to metabolize substance, such as sugar. Affects various organs and tissues, including the brain, and leads to early childhood death by age ten)

Published in the journal Nature April 2007 (and online): "PTC124 targets genetic disorders case by nonsense mutations" - New drug (PTC124) developed by PTC Therapeutics (South Plainfield, NJ - biotech firm): Targets or bypass nonsense mutations cause inherited diseases. The drug works by binding to a part of the cell called ribosome, translates genetic code into protein, and allows it to ignore nonsense mutations. Consequently, allowing cells to complete the correct sequencing to form a protein. The collaborative efforts between PTC Therapeutics, the University of Pennsylvania School of Medicine, and the University of Massachusetts of Medical School provided the resources, develop the new drug. W. Peltz, Ph. D., President and Chief Executive Officer of PTC Therapeutics said: "As these preclinical data demonstrate (Ongoing phase 2 clinical trials of PTC124 for Cystic fibrosis, Duchenne muscular dystrophy and number of additional genetic disorders), broad potential of PTC124 lies in its specificity and unique mechanism of action, which has the potential to address the underlying cause of a broad range of genetic disorders due to nonsense mutations." Journal Nature mentions PTC124 demonstrated production of dystrophin (during clinical trial), a protein made in cells of mice, previously absent and linked to Duchenee muscular dystrophy (DMD -- unable to maintain strength of muscle fibers.) Also, induces production of CFTR (cystic fibrosis transmembrane conductance regulator) missing protein in cystic fibrosis. Phase two clinical trials of PTC124, being studied at one of the Hadassah University Hospital in Jerusalem. Israel. Eitan Kerem, M.D., Head of Pediatrics and CF (cystic firbrosis) Center at the Hadassah University Hospital in Mount Scopus, Jerusalem said: "More then 60% of CF patients in Israel have CF due to nonsense mutation. Based on this clear demonstration of PTC124 activity we will be initiating a three - month study of PTC124 in patients with nonsense-mutation-mediated CF to further evaluate its potential for providing clinical benefit." Furthermore, the drug will undergo pediatric clinical trial in France. The medication is taken orally. The Food and Drug Administration granted PTC124 Fast - Track designation and Orphan Drug designation for the treatment of cystic fibrosis and Duchenee muscular dystrophy due to nonsense mutations. If phase two results prove successful (expected results first half of 2007): In 2007 more extensive trial will be undertaken (Phase 3), wider group of participants will be chosen, given higher doses and longer duration's, cooperating with regulatory authorities.

PTC Therapeutics said catalogued over 1,800 distinct genetic disease disorders (some of which are incurable) caused specifically by nonsense mutations, thousands of patients, could be treated. PTC124 should be available in Britain by 2009. Lee Sweeney of the University of Pennsylvania, who is leading the research said regarding PTC124: " What's unique about the drug is it doesn't target one mutation that cause disease, but a whole class of mutations." Appears to be safe during clinical trials in patients with DMD and cystic fibrosis. Also, drug appears to have no dosing interruptions or trial discontinuations due to toxicity. PTC124 will prevent early childhood deaths caused by Hurler's syndrome and cystic fibrosis and treatment for Haemophila, spinal muscular atrophy, neurofibromatosis, retintis pigmentosa, linked to nonsense mutations.