The first human clinical trial of a gene therapy treatment for Parkinson鈥檚 disease is set to begin in the US, following successful results in animals.
The treatment almost completely abolished the jerky movements associated with the disorder in half of a group of mice, a team led by Matthew During of the University of Auckland showed.
The treatment involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). A loss of dopamine-producing cells in the brains of Parkinson鈥檚 patients causes over-activity in the STN, which in turn causes jerky movements. But when the cells take up the gene, their activity is suppressed.
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This about-turn in the region reduces tremors, and even protects remaining dopamine-producing cells. 鈥淪o we鈥檙e hoping this approach will not only relieve symptoms but slow down progression of the disease as well,鈥� During told 快猫短视频.
The approach is 鈥渧ery novel and very clever鈥� says Roger Barker, an expert on Parkinson鈥檚 at the University of Cambridge, UK. But he believes it is too soon to start clinical trials in people.
Re-engineered circuitry
The gene used leads to the production of an enzyme called glutamic acid decarboxylase (GAD), which catalyses the production of a neurotransmitter called GABA. GABA acts as a direct inhibitor on the overactive cells in the STN. 鈥淲e鈥檙e giving these cells a new ability 鈥� and we鈥檙e doing it with a single gene,鈥� During says.
Barker says: 鈥淭o re-engineer circuitry in the region in a rather subtle way and produce a benefit from that is a very interesting approach.鈥�
During鈥檚 team injected the modified gene directly into the STN of rats. GABA was released not only in the STN but also in other parts of the brain reached by cells projecting from the region.
These included the substantia nigra, the site of the mass death of dopamine-producing cells in patients with Parkinson鈥檚. Increased GABA in the substantia nigra seems to account for the slowed cell loss seen in the experiments, says During.
Circuit fiddling
During thinks his approach is preferable to transplanting fetal dopamine-producing cells or stem cells into patients鈥� brains: 鈥淭he problem with all dopamine replacement approaches is that they can result in unregulated dopamine production. That鈥檚 a very bad thing to have 鈥� it can itself cause tremors.鈥� This problem has already been seen in patients who received fetal cell transplants.
During鈥檚 team also tested the safety of the gene therapy technique in primates, and found no toxic effects. As a result, they have FDA approval to try the treatment in 12 Parkinson鈥檚 sufferers.
The surgery will be performed by co-researcher Michael Kaplitt at Weill Cornell Medical College. Patients will be followed up for up to five years, though it should be apparent within one month whether the treatment is having an effect, says During.
But Barker says longer-term work on animals should be carried out before the therapy is tried on people. 鈥淭here is the worry that once you鈥檝e fiddled with these circuits, there could be compensatory changes in other parts of the circuit, which might produce unforeseen effects. I would be reluctant to say this should go to clinical trials yet,鈥� he says.
Journal reference: Science (vol 298, p 425)