Gene therapy could offer a new, long-lasting way to treat Parkinson's disease, research results announced Tuesday 15 July at FENS 2008 suggest. Dr Deniz Kirik of the University of Lund in Sweden has been using viruses to insert a new combination of genes into animals' brains, where they help produce the dopamine that is lacking in Parkinson's disease. The results suggest the treatment is very effective in animal models for several months, possibly years.
Parkison's disease (PD) is one of the most common brain disorders, affecting about 1% of people over the age of 65 years. It is a progressive neurological condition that primarily affects movement, but also other important functions such as cognition. It is caused by the loss of neurons (brain cells) in a region of the brain called the substantia nigra. These neurons produce dopamine, which allows messages to be sent to the parts of the brain that co-ordinate movement. As the dopamine-producing cells are lost, the brain areas that control movement can no longer function normally, leading to symptoms such as hand tremor and slowness of movement. Current drug treatments focus on increasing the levels of dopamine in the brain but can result in unwanted side-effects - something that this new technique could eliminate.
Dr Kirik's technique involves inserting two genes into the brain using a virus as a carrier or vector. Once the virus is inside the brain it infects brain cells and transfers the new genes to these cells. The new genes then produce two enzymes known as TH and GCH1 that combine with another enzyme, AADC, already present in the brain, and allow dopamine to be made at the appropriate sites. "The enzymes are synthesised in the brain cells and this helps the patients to regain the ability make dopamine," explains Dr Kirik.
It might sound dangerous to infect the brain with a virus but this one's been specially designed for the task. "These viral vectors are engineered so they cannot replicate, they cannot cause any diseases," says Dr Kirik. And in fact the virus used in this technique is one that doesn't cause disease in humans, known as adeno-associated virus, AAV. "From that point of view it's a safe virus vector to start with," says Dr Kirik. The viruses are purified, concentrated and then injected into the areas of the brain that are involved in dopamine delivery. "The dopamine neurons actually sit in another area of the brain, but they send their axons [cell projections] to this region, the striatum, and that's where they release the dopamine," explains Dr Kirik. "We insert the genes into another population of cells that are sitting in the target area, and then they become local mini pumps [for the dopamine]."
The key aspect of this new gene therapy method is that it could be a long-lasting treatment. "Once the vector is injected, the genes will be inserted into the cells and that will be there permanently," says Dr Kirik. And already the results are looking very promising. "From animal studies, both in rodents and monkeys, we think it will work for several years, at least for five years, probably longer," he says. This is a major step forward in treating PD because many patients who have the disease for years enter a phase where they do not respond well to current treatments any more. "Although they will survive anywhere between five, ten, 15 years beyond that point, their [treatment] options are limited," says Dr Kirik. "This is the population we can offer a better therapy, a higher quality of life."
The next stage for this research is for Dr Kirik's team to carry out further studies in primates. They're also working on developing the best clinical techniques to use in their studies and Dr Kirik hopes they may be able to begin human trials in the next two to three years. Other teams are using similar techniques to Dr Kirik's group, delivering different combinations of genes into the brain. One group is using three different genes together, while another team is using only one. "The superiority of one approach over the others will most likely be demonstrated in the first clinical trials as information from animal models cannot give us the final word," says Dr Kirik.