Research News

Thursday 4 March 2010

Preliminary results of ataluren clinical trial for Duchenne not encouraging

Preliminary results of the ataluren (previously known as PTC124) clinical trial for Duchenne muscular dystrophy have been announced. The international trial involved 174 boys with Duchenne muscular dystrophy caused by a specific type of fault in the genetic code called a nonsense mutation. This type of mutation is the underlying cause of 10-15% of Duchenne cases. To measure whether ataluren had improved muscle function in these boys, the distance they could walk in six minutes was measured throughout the 48 week trial. Unfortunately no difference in the distance walked was found between those receiving ataluren and those on placebo. There were no problems with the safety of ataluren during the trial.

The six minute walking test is considered a reliable way of measuring muscle function in Duchenne muscular dystrophy and was therefore chosen as the main outcome measure for the trial. The trial collected a lot of other data which has not been analysed yet, including activity at home, muscle and heart function, strength, cognitive ability, muscle integrity, and muscle dystrophin expression. PTC Therapeutics and Genzyme, the pharmaceutical companies conducting the trial, will release the results this data analysis in coming months.

Background information

Ataluren is an orally administered investigational drug that targets a specific type of mutation in the genetic code, called a nonsense mutation. The mutation creates a premature stop signal within a gene and therefore production of a complete functional protein is interrupted. Approximately 10-15% of Duchenne muscular dystrophy cases are caused by a nonsense mutation in the dystrophin gene. The dystrophin gene contains the instructions for an essential muscle protein which protects muscles from damage when they contract.

The 174 boys participating in this phase IIb clinical trial of ataluren were enrolled at clinics in North America, Europe, Australia, and Israel. In the UK the trial centres were in London, Oswestry and Newcastle. Participants were randomly chosen to receive either a low dose of ataluren, a high dose of ataluren, or placebo (inactive drug). The trial was 'double-blind', which means that neither the clinicians giving the drugs nor the trial participants themselves knew whether they were taking ataluren or a placebo. It was only after the trial was completed and the data analysis began that the code was broken to tell the researchers who was taking the drug and who was not.

Frequently asked questions

When will we know more about the rest of the results of the trial?
Clinical trials produce huge amounts of data which can take some time to analyse. Genzyme and PTC Therapeutics have assured us that they will analyse the results as quickly as possible and will keep us informed. They are keen that the clinical trials process is transparent and open throughout. Further announcements of results are expected in the coming weeks and months. We will post any more information we receive promptly on our website so please check back regularly.

What will happen to the other clinical trials currently in progress for Duchenne muscular dystrophy, such as the one for older, non-ambulant patients?
We don't know as yet. If you are involved in a clinical trial of ataluren please contact the clinician at your clinical trial centre for more information.

Do these results have any impact on the other clinical trials for Duchenne such as the exon skipping trial?
No, ataluren works in a different way to other therapeutic approaches currently in clinical trial. It is important that several different approaches are investigated at the same time to maximise our chances of finding an effective treatment.

Wednesday 3 March 2010

Spinal muscular atrophy gene therapy breakthrough

US scientists have successfully treated a mouse model of spinal muscular atrophy using a gene therapy approach. Day-old mice injected with a virus containing the gene missing in these mice (SMN1) were shown to survive for more than 250 days compared to the average 13-day lifespan of their untreated counterparts. They were also able to move around almost as well as normal mice. However, the treatment was only successful if administered within the first two days of life. The researchers hope that after further safety tests in the laboratory, the stage will be set for clinical trials of this gene therapy approach.

Spinal muscular atrophy is caused by the lack of a protein called 'survival of motor neuron 1' (SMN). This protein is essential for the survival of the motor neurons - the nerves which control the movement of muscles. People lack SMN protein if they have two faulty copies of the SMN1 gene, which contains the instructions for its production.

One approach with the potential to be developed into a treatment for spinal muscular atrophy is gene therapy that uses a virus to introduce a healthy copy of the SMN1 gene into cells. Adeno-associated viruses (AAVs) are an attractive virus to use because they are able to infect human cells but are not associated with any disease, and usually only cause mild immune reactions.

What did the research show?

The researchers in Ohio led by Dr Brian Kaspar injected AAV containing the SMN1 gene into a vein of mice lacking both copies of the SMN1 gene. These mice are severely affected by spinal muscular atrophy, only surviving for around 13 days. The treated mice survived for at least 250 days and were still alive when the results of the study were published. This is a remarkable improvement since previously tested drug-based approaches have only managed to increase the lifespan of these mice to around 40 days.

The researchers also tested the muscle function of the mice treated with the AAV. The motor ability of the mice was tested by placing them on their sides and measuring how long it took them to turn themselves onto their feet. None of the untreated mice were able to right themselves within 30 seconds, but 90% of 13-day-old treated mice were able to turn over within this time limit. The treated mice were also shown to move around and run on their wheel almost as much as normal mice. Examining the nerves of the treated mice found that they functioned almost as well as those of normal mice by the time they were three months old. However, the treated mice were only half the normal weight.

This study reported a narrow window of opportunity for treating the SMA mice with AAV. Treatment of one- and two-day-old mice was the most successful, whereas treating five-day-old mice only increased the average life span by about two days. Treatment was unsuccessful in 10-day-old mice.

To test whether the virus would also be able to pass into the nervous system of humans, a one-day-old monkey was injected with an AAV virus that produces a protein that is easy to see because it is fluorescent green under UV light. The florescent green protein was found in the motor neurons of the monkey, which bodes well for the treatment of humans. The researchers said that further studies are required to determine how early babies with spinal muscular atrophy would need to be treated by this approach.

What does this mean for patients?

This study shows the great potential of this AAV gene therapy approach to be developed into a treatment for spinal muscular atrophy. Previously scientists were sceptical that gene therapy would be possible for spinal muscular atrophy because the virus would need to penetrate into the relatively inaccessible nervous system. This study however showed that if treated early enough, mice were very successfully treated using this approach. The researchers commented that early identification of babies affected by spinal muscular atrophy using newborn screening might be paramount to the success of this gene therapy.

Several barriers will need to overcome before this potential treatment can be tested on humans. There are more than 10 clinical trials of AAV gene therapy for other conditions currently underway; however so far none have successfully reached the clinic and none have included infants. Further tests on the safety of this new technology will need to be carried out before the researchers can apply for permission to start the first clinical trial. Even so, they are hopeful that clinical trials will start within the next two years.

Information courtesy of the Muscular Dystrophy Campaign

http://www.muscular-dystrophy.org/#tab1