Promising New Approach To Treating Genetic Disorders Reveals
Duchenne Muscular Dystrophy
New preclinical data published online in the current edition of the journal Nature show that PTC124, an investigational new drug designed to bypass nonsense mutations, was efficacious in a preclinical model of Duchenne muscular dystrophy (DMD).
It is estimated that approximately 13 percent of the cases of Duchenne muscular dystrophy are due to nonsense mutations. PTC Therapeutics, Inc., which discovered and is developing PTC124, has catalogued over 1,800 distinct genetic disorders where nonsense mutations are the cause of the disease in a significant percentage of patients. Nonsense mutations inactivate gene function and are known to cause anywhere from five to 70 percent of the individual cases of most inherited diseases, such as cystic fibrosis (10%) and Hurler's syndrome (70%).
"We are pleased that the Nature paper offers an opportunity for us to describe our novel approach to regulating post-transcriptional control processes," said Stuart W. Peltz, Ph.D., President and Chief Executive Officer of PTC Therapeutics. "As these preclinical data demonstrate, the 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."
Dr. Peltz continued, "In addition to the ongoing Phase 2 clinical trials of PTC124 in cystic fibrosis and Duchenne muscular dystrophy, we are evaluating PTC124 in a number of additional genetic disorders."
Post-transcriptional control processes are the cellular regulatory events that take place after an RNA molecule is copied from DNA. These processes are critical to proper cellular function and provide an opportunity for therapeutic intervention through the modulation of protein levels.
Genetic disorders, such as Duchenne muscular dystrophy and cystic fibrosis (CF) are caused by genetic alterations, known as mutations. By targeting a specific type of genetic alteration -- nonsense mutations -- PTC124 bypasses the defect and leads to the restoration of a functional protein. The Nature paper highlights the data obtained from PTC's work in a mouse model of DMD in which a nonsense mutation precludes the production of dystrophin. Loss of functional dystrophin, an important muscle protein involved in maintaining the strength of muscle fibers, results in DMD. The data demonstrate that PTC124 allows dystrophin to be made in cells in which it was previously absent, to be delivered to the proper cellular location, and to induce restoration of muscle function. In addition to the studies described in the Nature paper, PTC has demonstrated in preclinical studies that PTC124 restores the presence of the missing protein in CF caused by nonsense mutations. Similar to the effect in DMD, PTC124 induces production of CFTR (the missing protein in CF).
The paper entitled, "PTC124 targets genetic disorders caused by nonsense mutations" is available in an advanced online publication of Nature on Sunday, April 22nd (http://www.nature.com). This publication is the result of collaborative efforts between PTC Therapeutics, the University of Pennsylvania School of Medicine, and the University of Massachusetts Medical School.
PTC124 is an orally delivered investigational new drug in Phase 2 clinical development for the treatment of genetic disorders due to nonsense mutations. Nonsense mutations are single-point alterations in the genetic code that introduce premature stop codons in RNA, which halt the translation process, producing a shortened, non-functional protein. PTC124 has demonstrated activity in preclinical genetic disease models harboring nonsense mutations, allowing the readthrough of premature stop codons and the restoration of the production of full-length, functional proteins. In Phase 1 clinical trials, PTC124 was generally well tolerated, achieved target plasma concentrations that have been associated with activity in preclinical models, and did not induce readthrough of normal stop codons. PTC is currently conducting Phase 2 clinical trials of PTC124 in nonsense-mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.
The FDA has granted PTC124 Fast-Track designations and Orphan Drug designations for the treatment of CF and DMD due to nonsense mutations. PTC124's development is supported by grants from the Muscular Dystrophy Association (MDA), Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT), Parent Project Muscular Dystrophy (PPMD), FDA's Office of Orphan Products Development (OOPD), the National Institutes of Health, and by General Clinical Research Center grants from the National Center for Research Resources (NCRR).