Clinical trials Medicine Science

Things like this make medical science worthwhile: A drug to treat genetic diseases due to nonsense mutations

There are times when, as a scientist, I look at an idea and its execution and simply stand in awe. It’s particularly satisfying when it’s a relatively simple idea that could conceivably do a lot of good for a lot of patients. Oddly enough, whether it’s because I’ve been out of the loop or because it hasn’t garnered that much attention in the blogosphere (not even here in ScienceBlogs), but I only just heard of it now. It’s a new drug in phase II clinical trials that has the potential to obviate or reverse the effects of a wide variety of genetic mutations that cause human disease:

A pill that can correct a wide range of faulty genes which cause crippling illnesses should be available within three years, promising a revolution in the treatment of thousands of conditions.

The drug, known as PTC124, has already had encouraging results in patients with Duchenne muscular dystrophy and cystic fibrosis. The final phase of clinical trials is to begin this year, and it could be licensed as early as 2009.

As well as offering hope of a first effective treatment for two conditions that are at present incurable, the drug has excited scientists because research suggests it should also work against more than 1,800 other genetic illnesses.

PTC124 targets a particular type of mutation that can cause very different symptoms according to the gene that is disrupted. This makes it potentially useful against a range of inherited disorders.

Basically, this drug works against what are called nonsense mutations. DNA provides the information necessary to produce proteins. It is made up of individual building blocks called nucleotides, while protein is made up of individual building blocks known as amino acids. The way that the genetic code in DNA is translated into proteins, which form enzymes, structural proteins, and proteins that carry out virtually every function necessary for life, is through large protein complexes called ribosomes. Ribosomes “read” the DNA, whose code is based on three-nucleotide sequences called codons, each of which codes for a different amino acid. Given four nucleotides and triplets, there are 64 possible codon combinations for 20 amino acids, which means that the genetic code is “degenerate”; i.e., most amino acids are coded for by more than one codon. There is a set of three codons, however, that do not code for any amino acid. They are known as stop codons, because when the ribosome encounters them it interprets it as a signal that the protein chain should end. When a mutation causes a codon to change from a normal codon that codes for an amino acid to a stop codon, it is known as a nonsense mutation, and it results in the termination of the protein chain wherever the mutation occurs.

There are a number of genetic diseases where the inherent defect is a nonsense mutation that causes the premature termination of the synthesis of the protein chain of the protein that is the cause of the disease. Among these are Duchenne’s muscular dystrophy and cystic fibrosis, both big killers. Cystic fibrosis, for example, results from mutations in a protein (CTFR) that cause impaired or nonexistent function of a chloride channel. The end result of this malfunctioning channel is the thick, sticky mucous that causes all the pulmonary problems such as recurrent pneumonias, as well as GI and pancreatic problems. In the case of muscular dystrophy, there are a number of mutations than can cause the disease in varying degrees of severity, among these nonsense mutations, and approximately 13% of muscular dystrophy is due to nonsense mutations. If a way could be found to “read through” the aberrantly produced stop codons responsible for these and many other genetic diseases, it might be possible to greatly reduce or even eliminate the symptoms of as many as 1,800 genetic diseases. In replacing many of the proteins involved in these diseases, 100% efficiency is not needed, because in the case of some diseases if the normal protein can be restored to only 1-5% of its normal level, considerable improvement in symptoms could be caused.

But how might it be possible to cause the cell to “ignore” stop codons produced by It turns out that there is a pathway, known as nonsense-mediated mRNA decay (NMD)), by which messenger RNA containing premature stop codons is selectively destabilized and degraded. As Neu-Yilik et al describe in a recent review:

Nonsense-mediated mRNA decay (NMD) is a specific pathway for the degradation of mRNAs that have premature termination codons (PTCs) in their open reading frames (ORFs). Its importance is highlighted by its conservation in all eukaryotes. NMD counteracts the potentially harmful impact of mRNAs that have PTCs as a result of errors at various levels of gene expression, such as nonsense and frameshift mutations, transcriptional errors and faulty splicing. Thus, NMD serves as a ‘cellular vacuum cleaner’ that protects the cell from the potentially harmful effects of truncated proteins by eliminating mRNAs with PTCs in a sequence of events that is not yet fully understood.

Investigators from PTC Therapeutics in New Jersey, the University of Pennsylvania, and the University of Massachusetts used a high throughput screen to look at 800,000 low molecular weight compounds to identify ones that promoted nonsense mutation suppression. This is some heavy duty medicinal chemistry and a very impressive effort. One compound that they identified (PTC124, chemical structure pictured below) was the most potent and selected for further screening.


This compound was very potent at promoting readthrough of nonsense mutations in cell culture using primary cultured muscle cells harboring a nonsense mutation in the dystrophin gene, mutations in which can cause Duchenne’s muscular dystrophy. It was then tested in a mouse model of muscular dystrophy. These mice, known as mdx mice, have a mutation in the dystrophin gene. Lack of functional dystrophin results in increased susceptibility to contraction-induced injury, leading to ongoing cycles of injury and regeneration, inflammation, and necrosis, with the ultimate destruction of the involved muscles. Treating these mice, either with oral feeding or intraperitoneal injection of PTC124, significantly reversed the functional abnormalities normally seen in the muscles of mdx mice associated with increased dystrophin production to levels approximately 25% of what is observed in normal mice. I can see why this paper was published in Nature.

The drug has already made it through two phase I clinical trials, with minimal toxicity. The most troublesome side effects were transient flatulence that did not recur even if dosing was continued (I kid you not), headache, nausea, and dizziness. In addition, some patients had mild reversible elevations in their liver enzymes and more signficant elevations of muscle enzymes (creatine kinase) in three subjects. However, the investigators could find no correlation with dosing of the drug and concluded that these elevations were probably due to exercise-induced muscle injury. Better, no evidence of nonspecific readthrough of normal stop codons was observed. Presently, a phase II study is being completed, and, according to reports, will be published soon; initial descriptions suggest that there are “promising” results in patients with muscular dystrophy and cystic fibrosis.

As has been pointed out elsewhere, although this drug gives children with muscular dystrophy and cystic fibrosis hope that their condition might be effectively treated at its cause, rather than just treating the complications, it is important to emphasize that one critical aspect of this new class of drugs is that they will make it imperative that a patient’s specific gene mutation has been identified by sequencing. PTC124 only has the potential to work for nonsense mutations; if the gene mutation involved is not a nonsense mutation, PTC124 will not work.

I also have to voice a word of caution here, much as I have done with dichloroacetate (DCA), the small molecule cancer chemotherapy drug that was hyped as a cheap “cure” for cancer. Although this drug has made it much farther than DCA has thus far, having gone beyond animal studies, it still might fail. We will have to await the final results of phase III clinical trials, but, given that nature of this treatment, such trials can be carried out considerably faster than cancer trials because overall survival does not have to be measured to show that the drug is efficacious enough to be approved. Improvement in symptoms and demonstration of the return of the production of the full-length protein with the nonsense mutation, and likely that would be enough, with long term trials looking at improvements on survival to be done later.

It’s very likely that PTC124 will be only the first among an entirely new class of small molecule orally available drugs to treat genetic diseases. If it proves successful in clinical trials, we may be on the cusp of a new age of therapies that make genetic diseases, once considered untreatable, into manageable diseases. True, it would require patients to take a pill every day for the rest of their lives, but, compared to the ravages of diseases like cystic fibrosis or muscular dystrophy, that’s a small price to pay.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

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