The neuron misfirings that lead to the major symptoms of Parkinson’s disease (PD) result from a loss of dopaminergic neurons that may be related to an imbalance of neurotransmitters in the brain. In today’s Science, researchers from New Zealand and the U.S. report a gene therapy that can relieve symptoms of Parkinson’s disease in animal models by correcting that imbalance.
Led by Matthew During, University of Auckland, the scientists succeeded in transferring genes for glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN) of rat brains. The rationale behind this approach was to decrease the excitatory activity of the STN by increasing the levels of the inhibitory neurotransmitter GABA (γ-aminobutyric acid), the product of GAD activity. Previously, inhibition of the STN by ablation, drugs, or electrical means, has been shown to relieve PD symptoms.
Together with colleagues from Jefferson Medical College, Philadelphia, and Cornell University, New York, first author Jia Luo used recombinant adeno-associated viruses, stereotactically implanted into the STN, to deliver the genes. Five months after surgery the animals had robust expression of GAD in the STN of the ipsilateral (transfected), but not the contralateral (untransfected), side of the brain.
The authors next tested the functionality of the transfected genes by treating the animals with 6-hydroxydopamine. This derivative of dopamine induces degeneration of dopaminergic neurons, leading to a Parkinson’s-like phenotype. Using microdialysis the authors showed that when the STN is stimulated, levels of GABA in the substantia nigra, which is innervated by the STN, are significantly higher in transfected animals than in controls. In fact, the numbers of neurons inhibited in the substantia nigra dramatically increased (78 percent versus only three percent in controls) when the animals had been transfected with the gene for the GAD65 isoform.
GAD65 was also capable of abrogating, by 65 percent, impaired locomotor activity associated with 6-hydroxydopamine denervation of midbrain dopaminergic neurons. This attenuation correlated with increased survival of dopaminergic cells. In the substantia nigra pars compacta and the ventral tegemental areas of the midbrain, 35 and 80 percent of cells survived, respectively, in transfected animals, versus only about 7 percent survival for both regions in control animals.
These studies indicate that gene transfer may be a viable means of controlling Parkinson’s disease in humans (see also related news item and item). The major hurdle, of course, lies in overcoming the complications associated with this type of therapy. The halting of recent gene therapy trials because of serious, and in one case fatal, complications poses a challenge to bringing such promising approaches into the clinic (see Oct 4 New York Times).—Tom Fagan
No Available Further Reading
- Luo J, Kaplitt MG, Fitzsimons HL, Zuzga DS, Liu Y, Oshinsky ML, During MJ. Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science. 2002 Oct 11;298(5592):425-9. PubMed.