Case study: Researcher Z
Research: Finding new treatments for Duchenne muscular dystrophy, where currently no treatment is available.
Animals used: Mice
Researcher Z (prefers to remain anonymous): ‘There is no effective treatment for Duchenne muscular dystrophy, the most common genetic form of muscular dystrophy.
‘About 100 boys are born with the disease in the UK every year. While they have no symptoms at birth, by four or five they have difficulty walking up stairs, by age 12 they are in a wheelchair, and they die in their late teens or twenties.
‘The disorder is caused by genetic mutations that result in the lack of a protein called dystrophin which is normally present in muscle cells. The progressive muscle weakness seen in boys with Duchenne muscular dystrophy arises as muscle cells die and cellular debris gradually builds up and accumulates. The dystrophin gene shows the highest mutation rate in humans, meaning that new mutations arise all the time and screening all pregnancies for mutations is difficult.
‘The devastating effects of Duchenne muscular dystrophy really shows the need for new therapies. In the past three to four years some new approaches have emerged, including from my own research group. Next year, the approach that we have developed is being taken into the first clinical trials by a US pharmaceutical company.
‘In 1989, we showed that muscle cells possess another protein similar to dystrophin called utrophin, although it is not present in high enough amounts to replace the lack of dystrophin in boys with the condition. We believed that if we could increase the levels of utrophin, we might have a new treatment approach.
‘There is some evidence that utrophin is present in the early foetus at levels comparable to dystrophin, so we believed it should be possible. We have now shown that we can increase the amount of utrophin and cure the disease in a mouse model.
‘However, we never put drugs in animals unless they have been optimised in cell lines in the lab in the first place. We do as much as we possibly can in cell lines.
‘We began by screening compounds to see if they could interfere with cell machinery in a way that would lead to increased utrophin levels. This was in a spin-out company I formed. Perhaps 30,000 compounds were screened, resulting in around 30 ‘hits’. We then optimised these 30 promising compounds in cell lines, which gave 3 potential drug compounds we could test in mice.
‘Before we moved into mice, the company screened the drugs for toxicity in zebrafish. The development of zebrafish is very sensitive to the toxicity of compounds. This is a relatively new way of screening out potentially toxic compounds, reducing the number of mice used later.
‘By doing all this work, we learnt more about the biology and we have been able to refine what we do as our knowledge increases. At the start, we used ten mice in each trial group. Now we can use six.
‘Now we are moving into human clinical trials, which will start in early 2010. If our first trials show good results, we will then try to raise money for improving the chemistry and optimising the drug, making it a more efficient treatment.
‘The mouse model has a point mutation in the dystrophin gene, but the mouse is only very mildly affected by this. You wouldn’t be able to tell it was affected in any way by watching the mouse alone. Only under a microscope can you see that the muscles are affected. We breed these mice and they are perfectly happy. The drug that we have been testing is injected as we find that gives more reproducible results than when the mice are fed the drug in a food pellet.
‘Before, in our old animal facilities, we didn’t have optimal conditions although they were perfectly fine. This meant reproducibility in experiments was a challenge and we needed to test large numbers of mice. The uniformity of the environment in the Biomedical Sciences Building means there is a low risk of infections, the health of the animals is better, and so the chances of the drugs working is much better. It's been a significant improvement for the animals and for the research.’