Apr 23, 2007
A drug that offers the first real hope for around ten per cent of patients who suffer the common genetic disorders Duchenne Muscular Dystrophy and cystic fibrosis has been unveiled.
Beneficial effects are reported in studies on mice and the drug is now being tested on more than 100 patients, with initial data suggesting that it could offer the first treatment for the underlying disease.
Perhaps most remarkable of all is that the drug could also help a significant fraction of sufferers of around 2,000 other types of hereditary disease.
Genetic disorders such as the muscle wasting disease Duchenne Muscular Dystrophy and cystic fibrosis, the most common of all among Caucasians, are caused by genetic alterations, spelling mistakes in genes. Every gene is a stretch of DNA code that contains the recipe for a protein in the body, from enzymes to hormones and many more besides, and the mutations have a range of effects, depending on where they are in the gene's DNA, from a "nonsense" mutation that means the protein is not made at all, to mutations that make a non functioning protein and even those that make a harmful protein.
Now a team from a biotechnology company and the Universities of Pennsylvania and Massachusetts announces in the journal Nature that a drug which targets the effects of nonsense mutations in a new way has shown great promise in both animal models of disease and in human trials, offering new hope for around one in ten sufferers of cystic fibrosis, which affects approximately one of every 3,500 live births, and Duchenne Muscular Dystrophy, which affects around one of every 3,500 male children.
The drug - PTC124 - overcomes the defect and leads to the restoration of a working protein. The experimental drug was shown to successfully bypass a nonsense mutation in mice so that they are able to make the muscle protein dystrophin.
Loss of working dystrophin protein, involved in maintaining the strength of muscle fibres, was reversed, the team reports in Nature The data show that PTC124 allows dystrophin to be made in cells in which it was previously absent and to induce restoration of muscle function.
Although many different kinds of mutation cause the disease, the work is significant because it is estimated that approximately 13 percent of patients suffer due to nonsense mutations. In addition to the studies described in the Nature paper, other work suggest that PTC124 restores the presence of the missing protein that causes cystic fibrosis in patients with nonsense mutations.
Once again, PTC124 induces production of a protein called cystic fibrosis transmembrane conductance regulator, CFTR, which was missing as a result of nonsense mutations.
The New Jersey based company PTC Therapeutics, Inc., which discovered and is developing PTC124, has catalogued over 1,800 distinct genetic disorders where nonsense mutations are the cause in a significant percentage of patients. They cause anywhere from five to 70 percent of the individual cases of most inherited diseases, such as cystic fibrosis (10 per cent) and Hurler's syndrome (70 per cent).
"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," said Stuart Peltz, President and Chief Executive Officer of PTC Therapeutics, and senior coauthor of the Nature paper.
Aside from evidence that missing proteins were being made in the patients, there was anecdotal evidence of benefit. The family of one boy in Israel said he had slept through his first night without coughing.
"In the case of muscular dystrophy, we had reports of kids who were more active," he told The Daily Telegraph. But he stressed that bigger, randomized control studies, are now needed to quantify the effects. 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 preclinically in a number of additional genetic disorders."
Nonsense mutations are single spelling mistakes in the genetic code that, when read by cellular machinery, mark a "full stop" in the process of turning genetic code into one of the proteins that builds and operates cells.
This prematurely interrupts the process of making the proteins, creating fragments of proteins without function and ultimately resulting in genetic disorders and disease. PTC124 is a small molecule that allows the biochemical machinery to skip these full stops to restore the manufacture of the protein. The drug acts on the ribosomes, the "factories" that make the proteins that build and operate cells.
Dr Peltz said that in some hereditary diseases even if only one per cent of protein is made as a result of the drug's action, there can be a significant effect. Often as little as 10 per cent of normal protein is enough to halt the condition. I
n Phase 1 - preliminary, clinical trials, PTC124 was generally well tolerated, achieved concentrations in the body that have been associated with activity in animals. One fear was that the normal full stops in the genetic code could be ignored, causing side effects. But there was no evidence of this, said Dr Peltz.
PTC has had approval from the US authorities to carry out larger - Phase 2 - clinical trials of PTC124 in nonsense-mutation-mediated cystic fibrosis and Duchenne muscular dystrophy. Last year, at an international conference in London, the company reported increases in dystrophin in muscle biopsies in a number of patients and statistically significant improvements in muscle enzymes.
"These results are the first example of an oral therapy addressing the underlying cause of DMD by restoring dystrophin production," said Dr Richard Finkel, Children's Hospital of Philadelphia, one of the lead investigators of the trial on 26 patients. "There are limited therapeutic options for patients living with DMD, and these data strongly indicate PTC124 warrants further clinical investigation in this patient population, which has a great unmet medical need." Patients included in the interim analysis were enrolled at three clinical sites in the United States: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Cincinnati Children's Hospital Medical Centre, Cincinnati, Ohio; and the University of Utah, Salt Lake City, Utah.
In the study, patients received 28 days of PTC124 treatment at one of two dose levels. All patients were boys with a nonsense mutation in the dystrophin gene.
Patients with cystic fibrosis lack the CFTR protein that maintains proper hydration of cells in the lung, pancreas, and liver, triggering viscous secretions that result in inflammation, chronic colonisation by bacteria and progressive organ destruction. Patients experience chronic shortness of breath, coughing and production of thick, sticky sputum.
In two Phase 2 clinical trials in around 40 patients with cystic fibrosis due to a nonsense mutation, one in America and one in Israel, doctors found that PTC124 can restore function of the (CFTR) protein in airway cells. "These results are very exciting because they provide the first indication that an oral therapy may address the underlying cause of CF through restoration of CFTR function," said Dr J.P. Clancy, University of Alabama at Birmingham, and the lead investigator.
Dr Eitan Kerem, at the Hadassah University Hospital in Mount Scopus, Jerusalem commented, "More than 60 per cent of cystic fibrosis patients in Israel have CF due to a nonsense mutation. Thus, we were very gratified to see such remarkable improvements in CFTR function and other parameters in just a two-week treatment period."