click to enlarge Translation of an mRNA into protein: comparison of normal translation, premature termination of translation, and treatment with ataluren inducing synthesis of functioning protein.

An investigational new drug, ataluren is a potential protein restoration therapy designed to enable the formation of a functioning protein in patients with rare genetic disorders caused by a nonsense mutation, such as nonsense mutation Duchenne and Becker muscular dystrophy (nmDBMD). DBMD, also known as dystrophinopathy, is a rare and life-threatening genetic disorder that primarily affects boys and young men. There are an estimated 1,900 patients with DBMD due to a nonsense mutation in the United States.

Patients with DBMD do not produce enough functional dystrophin, a protein that is critical to the structural stability of skeletal and cardiac muscles. As the disease progresses, patients may lose the ability to walk as early as age 10, and experience life-threatening heart and lung complications in their late teens and twenties. There are currently no drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of DBMD.

Ataluren is being developed by PTC Therapeutics, whose drug discovery technologies focus on post-transcriptional control processes that regulate the rate and timing of protein production.

In healthy individuals, ribosomes translate the informational code in messenger RNA (mRNA) until arriving at a normal stop signal, at which point the ribosome appropriately stops translation and a functioning protein results. Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, incomplete protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional. Ataluren is designed to allow the ribosome to bypass the premature stop signal and continue translation of the mRNA, resulting in a functioning protein.

In many genetic disorders, 10% to 15% of cases are caused by a nonsense mutation Ataluren has the potential to address the underlying cause of the disease in these patients. A Phase 2a clinical trial of ataluren in patients with nmDBMD showed that ataluren increased production of functional dystrophin and reduced leakage of muscle-derived creatine kinase into the blood. Results from a randomized, double-blind, placebo-controlled Phase 2b clinical trial of ataluren in patients with nmDBMD are expected in the first half of 2010.

PTC also recently initiated a pivotal Phase 3 clinical trial in nonsense mutation cystic fibrosis and plans additional late-stage trials in patients with other nonsense mutation genetic disorders.