Scientists target nonsense mutations with investigational new drug 

April 23, 2007 

WORCESTER, Mass. - In new data published in the journal Nature, investigators from the University of Massachusetts Medical School, the University of Pennsylvania School of Medicine and PTC Therapeutics report on the promise of an investigational new drug for the treatment of a large class of genetic disorders. Published April 22 in an advanced online publication, "PTC124 targets genetic disorders caused by nonsense mutations," describes the identification and characterization of the drug, PTC124, and its preclinical success in the treatment of Duchenne muscular dystrophy (DMD).  DMD is one of the most prevalent types of muscular dystrophy and is characterized by rapid progression of muscle degeneration early in life. DMD affects males-an estimated 1 in 3,500 boys worldwide. 

PTC124 is designed to bypass the genetic consequences of nonsense mutations-the cause of an estimated 13 percent of cases of DMD. Nonsense mutations in genes disrupt the function of messenger RNA (mRNA), which encodes and carries information from DNA to sites of protein synthesis. In normal function, the information in mRNA has a defined start and end to its genetic code. However, when a gene contains a nonsense mutation, the action of its mRNA is prematurely terminated by the presence of a "nonsense" codon. This premature molecular stop signal prevents a cell from deriving all of the information present in an mRNA, thereby leading to the synthesis of an incomplete (and nonfunctional) protein. PTC124 allows cells to ignore the premature molecular stop signal, leading to the synthesis of a complete protein. In the study described in the Nature paper, PTC124 was shown to restore the synthesis and function of the muscle protein dystrophin in animals and patients that harbored nonsense mutations in the dystrophin gene. Loss of functional dystrophin, an important protein involved in maintaining the strength of muscle fibers, results in DMD.  

In addition to demonstrating that PTC124 allows dystrophin to be made in cells in which it was previously absent, the investigators show that the newly synthesized dystrophin can be delivered to the proper cellular location to induce the restoration of muscle function.  Tested in animal models, the drug was also well tolerated and appears safe after initial investigation. Human clinical trials have been initiated with DMD and cystic fibrosis patients, and PTC Therapeutics will continue to evaluate PTC124 in a number of additional genetic disorders. 

According to University of Massachusetts Medical School (UMMS) Professor and Chair of Molecular Genetics and Microbiology Allan Jacobson, PhD, one of the paper's primary authors and a co-founder of PTC Therapeutics, the potential of PTC124 extends to other distinct genetic disorders caused by nonsense mutations. "We know of at least 1,800 distinct genetic disorders where nonsense mutations are the cause of the disease in a significant percentage of patients.  In bypassing the defect and restoring the production of functional proteins, PTC124 may be able to address and treat the underlying cause of a large number of genetic disorders for which there are presently no therapeutic options," Dr. Jacobson said. He also noted that "this is one of the first examples of 'personalized medicine,' where an individual's genetic makeup determines the nature of his or her medical treatment." 

UMMS Research Assistant Professor of Molecular Genetics & Microbiology Feng He, PhD, and Research Associate Phyllis Spatrick also contributed to this research. 

About the University of Massachusetts Medical School
The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $176 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine, hailed as the "Breakthrough of the Year" in 2002 by Science magazine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit 

About PTC Therapeutics, Inc.
PTC is a biopharmaceutical company focused on the discovery and development of orally administered, proprietary, small-molecule drugs that target post-transcriptional control processes.  Post-transcriptional control processes regulate the rate and timing of protein production and are of central importance to proper cellular function.  PTC's internally-discovered pipeline addresses multiple therapeutic areas, including genetic disorders, oncology, and infectious diseases.  In addition, PTC has developed proprietary technologies and extensive knowledge of post-transcriptional control processes that it applies in its drug discovery and development activities, including the Gene Expression Modulation by Small-molecules (GEMS) technology platform, which has been the basis for collaborations with leading pharmaceutical and biotechnology companies such as Pfizer, CV Therapeutics, and Schering-Plough.

Contact: Kelly Bishop, 508-856-2000