A ‘secret weapon’ for drug-resistant epilepsy

Epilepsy affects more than 60 million people worldwide, and at least 3.4 million people in the United States, including 470,000 children, have active epilepsy, according to the Centers for Disease Control and Prevention. Temporal lobe epilepsy, which affects the brain’s learning and memory center, called the hippocampus, is the most common type of acquired epilepsy.

In a person with epilepsy, the brain experiences repeated seizures, which are sudden bursts of electrical activity that result in involuntary changes in body movement or function, sensation, behavior or awareness. Antiepileptic drug treatments are somewhat effective in controlling seizures in just over 60 percent of people with epilepsy, but the other 40 percent experience uncontrolled seizures and what is called “drug-resistant epilepsy.” Surgical removal of the epileptic brain tissue–including the hippocampus–is a treatment for drug-resistant epilepsy, but there is a risk of developing permanent cognitive and memory problems following brain tissue excision. Therefore, alternate therapies for drug-resistant epilepsy are needed.

A team of researchers led by Ashok Shetty, PhD, professor and associate director for the Institute for Regenerative Medicine, Department of Cell Biology and Genetics at the Texas A&M University School of Medicine, recently demonstrated a potential alternative therapy in research published in the journal NPJ Regenerative Medicine. Shetty’s study demonstrated for the first time that transplanted inhibitory interneurons from human pluripotent stem cells could directly control seizures and improve cognitive function in an animal model of chronic temporal lobe epilepsy.

Increased electrical activity of a group of excitatory neurons—called glutamatergic neurons—causes most seizures. This increase occurs when certain inhibitory neurons (called GABA-ergic interneurons) are damaged in some way, often due to a brain insult, such as head injury or brain inflammation.

Therefore, in theory, transplanting GABA-ergic interneurons into the epileptic brain could potentially restore the excitation-inhibition imbalance to prevent seizures. However, the production of transplantable human GABA-ergic inhibitory interneurons has been one of the bottlenecks for putting this theory into practice. Also, the efficacy of such cell therapy to significantly reduce seizures had not before been tested in animal models exhibiting robust chronic epilepsy.

“This study has demonstrated that a type of human GABA-ergic inhibitory interneurons (in other words, medial ganglionic eminence, or MGE, interneurons) can be produced in unlimited quantities from human pluripotent stem cells,” Shetty said. “Also, the study revealed that transplantation of such neurons into the hippocampus can greatly dampen the occurrence of seizures and reverse memory deficits.”

The study showed that transplanted human GABA-ergic inhibitory neurons grew long axons that made appropriate connections (synapses) with the hyperactive glutamatergic neurons. “Such graft-host connectivity dampened the hyperactivity of glutamatergic neurons, which greatly reduced seizures,” said Dinesh Upadhya, PhD, the first author of the article who was a senior research associate in Shetty’s laboratory. He is currently an associate professor at the Center for Molecular Neurosciences, Manipal Academy of Higher Education in Manipal, India.

The researchers were able to switch the effect on and off by silencing or turning on the inhibitory neurons using a chemogenetic approach.

In addition, while transplantation of these GABA-ergic inhibitory interneurons improved memory formation and recall, silencing the activity of these transplanted neurons resulted in memory problems. Such a finding implies that transplanted human neurons control the memory functions of the hippocampus, in addition to controlling seizures.

“Transplanted human GABA-ergic interneurons can control seizures and improve memory function in a chronic temporal lobe epilepsy model, and because human GABA-ergic interneurons were used as donor neurons, the approach employed in the study could be translated to the clinic,” Shetty said.

Recently, the United States Food and Drug Administration (FDA) has approved a limited clinical trial using human MGE-type inhibitory GABA-ergic interneuron transplantation in drug-resistant temporal lobe epilepsy patients. “The current study provides a strong rationale for such a clinical trial,” Shetty added.

This study was supported by grants from the Department of Defense and the National Institute of Neurological Disorders and Stroke to Shetty.

 

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