A mutation makes mucus accumulate in cystic fibrosis patients' lungs.Getty

A drug that corrects the effects of a genetic mutation has produced encouraging results in tests on patients. The drug, PTC124, is designed to fool a patient's cells into producing a functional protein, even though that protein's gene is mutated.

PTC124, made by New-Jersey-based biotech company PTC Therapeutics, is part of a growing field of research targeting therapies at the RNA that ferries information between DNA and proteins. Although results so far are preliminary, they provide proof of principle that this kind of approach could work in people.

The drug, which can be taken orally, improved the function of a protein known as CFTR in a subset of patients with cystic fibrosis. CFTR transports chloride ions across cell membranes, maintaining the right level of hydration in tissues such as the lungs and pancreas. Mutations affecting the protein result in thick mucous clogging these organs, causing inflammation and chronic bacterial infections.

Cystic fibrosis is one of the most common serious genetic disorders, affecting around one in every 3,300 Caucasians as well as other groups. Sufferers have an average life expectancy of 37 years, and current therapies treat the disease's symptoms rather than its cause.

After PTC124 treatment, some patients' proteins showed signs of working normally. Some also reported easing of their symptoms. "I was very excited with the findings, especially hearing the patients say they felt better," says Eitan Kerem, an expert on cystic fibrosis who headed one trial at the Hadassah University Hospital in Jerusalem, Israel.

Stop!

Preliminary results from 42 adult patients in the United States and Israel were announced on 3 November at the North American Cystic Fibrosis Conference in Denver, Colorado. The trial was a phase-2 trial, in which a drug is tested on a small number of patients for a short time. Larger, phase-3 trials are needed to see how effective the drug is and whether there are any long-term side effects.

PTC124 targets only one kind of mutation, and so would not help all cystic fibrosis patients — only 10% of US sufferers have this mutation, for example. But the same kind of mutation can underlie many other genetic diseases, such as Duchenne muscular dystrophy. Phase-2 trials are underway in Duchenne patients.

To activate a gene, a cell copies its sequence into RNA, DNA's molecular cousin. The resulting molecule, called messenger RNA, or mRNA, forms a template for the protein. A set of RNA letters known as a stop codon appears at the end of the mRNA to end protein manufacture.

In some cystic-fibrosis patients, the instructions for the CFTR protein contain a stop codon in their middle. The mRNA is either destroyed (see 'Nonsense mutations: Running the red light') or it produces a shortened protein that usually doesn't work properly.

The drug PTC124 causes the cell's protein-making machinery to ignore the stop signal and, in lab and animal tests, produce a full-length protein. Other attempts to correct gene mutations, such as gene therapy, have largely depended on big, complex molecules such as DNA, RNA or proteins. But such drugs are difficult to deliver to the cells. PTC124 is a small molecule that is easily absorbed by the body.

Round of edits

Other researchers and clinicians are intrigued, but remain cautious. "It's certainly exciting to have a small molecule that addresses and affects genetic disease," says Andreas Kulozik, who studies genetic diseases at the University of Heidelberg in Germany. "That's certainly a major advance, if it does work."

Lynne Maquat, an RNA researcher at the University of Rochester, USA, says more research is needed. But she adds that there is a real need for drugs of this sort. An antibiotic called gentamycin also causes cells to ignore mutations, but it can cause deafness and kidney failure.

Other groups are developing different ways to target mutated RNA. One approach is to make the cell 'edit' a faulty stretch of sequence out while producing mRNA. Other tactics involve using drugs to boost the activity of faulty proteins; a number of these are nearing human trials. "There are many agents that are nearing studies in cystic-fibrosis patients," says Clancy.

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University of Heidelberg