What's the science?
Patients with epilepsy often do not respond to anti-epileptic drugs and continue to experience seizures. Drug-resistance is especially common when seizures arise from a specific region of the brain (focal epilepsy). Further, anti-epileptic drugs are not selective for the neurons which cause seizures. Viral mediated gene therapy, where new DNA is carried by a viral vector and inserted into cells, could potentially be used to selectively modify neuron populations that cause seizures. Gene therapy has shown promise in animal models; however, most therapies have been irreversible. This week in Nature Medicine, Lieb and colleagues use an autoregulating viral-mediated gene therapy treatment in rats to test whether it is tolerated and reduces seizures.
How did they do it?
They designed a viral plasmid containing a gene encoding a glutamate-gated chloride channel that detects excessive glutamate (an excitatory neurotransmitter) release from neurons and inhibits neurons in a self-regulating manner. Glutamate release is increased in epilepsy resulting in heightened neural activity, so inhibiting this process can reduce seizures. Adult rats were injected with pilocarpine, a seizure inducing drug, before injection of the viral vector containing the glutamate sensitive channel or a control vector, and then again two weeks later. Both of these were administered to the primary motor cortex of the rats. An electrode was also placed in the motor cortex to record the electroencephalogram (EEG) to detect seizure activity. Comparing the effect of pilocarpine before and after treatment revealed the effect of gene therapy on seizure activity. They then tested the effect of gene therapy on a model of chronic focal epilepsy where seizures occur spontaneously for several weeks after injecting tetanus toxin into the visual cortex of rats. They did this by comparing the frequency of seizures before and after treatment. Finally, they performed a series of behavioral experiments to test whether motor coordination was altered by the gene therapy treatment administered to the primary motor cortex (i.e. whether it was well tolerated).
What did they find?
Rats injected with the viral DNA encoding the glutamate sensitive channel showed a reduction in frequency and amplitude of seizure-related activity (induced by pilocarpine in the motor cortex), when compared to rats injected with the control virus. The frequency of spontaneous seizures was also reduced after introducing the glutamate sensitive channel in a chronic model of focal epilepsy. However, there was no effect on seizure duration or intensity in the chronic epilepsy model, or on the background EEG. These results suggest that the gene therapy was effective in inhibiting both pilocarpine-evoked seizure-related activity and the number of spontaneous seizures in a chronic focal seizure model. After testing for effects of gene therapy on motor coordination, there was no difference between control rats and those rats treated with the viral injection of the glutamate sensitive channel, demonstrating that the gene therapy was well tolerated.
What's the impact?
This is the first study to demonstrate how gene therapy can be used to express an autoregulating channel that responds to excessive glutamate release to reduce seizures. This gene therapy was well-tolerated and able to inhibit neurons to reduce seizure related activity and reduce the number of seizures in a chronic model of focal epilepsy. This study shows that gene therapy could potentially be used to apply selective treatment to specific brain regions causing seizures. Further research will be needed to ensure that this gene therapy can be well tolerated in humans.
Lieb et al., Biochemical autoregulatory gene therapy for focal epilepsy. Nature Medicine (2018). Access the original scientific publication here.