Stem Cell-Derived Neurons May Cut Recurrent Seizures

Michael Vlessides

December 31, 2018

Grafting autologous medial ganglionic eminence (MGE) cells may ultimately open the door to alleviating spontaneous recurrent seizures — and potentially provide permanent, patient-specific treatment of temporal lobe epilepsy, new research suggests.

Performing comprehensive video-electroencephalographic (video EEG) recordings and a battery of behavioral tests in a rat model, the investigators showed that grafting human-induced pluripotent stem cell (hiPSC)-derived MGE-like interneuron precursors into the hippocampus after status epilepticus (SE) greatly restrained spontaneous recurrent seizures.

The procedure also alleviated cognitive, memory, and mood dysfunction in the chronic phase of temporal lobe epilepsy.

"Antiepileptic drugs primarily suppress seizures, but they don't address or treat cognitive dysfunction and depression," co-investigator Ashok K. Shetty, PhD, professor of molecular and cellular medicine at Texas A&M College of Medicine, told Medscape Medical News.

"With this novel approach, however, we were not only able to bring about a substantial decrease in seizures, but also improved the animals' memory function and depression," Shetty added. "So it's a combination of benefits."

The findings were published online December 17 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Drug Treatment Limited

Antiepileptic drugs have proven effective for terminating most cases of SE, but drug therapy does not address epileptogenesis or the development of temporal lobe epilepsy, the researchers write. Long-term intake of antiepileptic drugs has also been linked to adverse side effects, leading to interest in alternative approaches, such as cell therapy.

This includes grafting MGE-derived GABA-ergic progenitor cells, which has received significant attention. The researchers note that the loss of GABA-ergic interneurons is a major pathological hallmark in both human and animal models of temporal lobe epilepsy.

Despite this potential, it is unknown whether MGE graft-derived cells are directly involved in suppressing spontaneous recurrent seizures.

The current researchers generated hMGE-like cells from hiPSCs through rapid directed differentiation, then transplanted these cells into the hippocampus of rats that underwent kainate-induced SE, a common model of human temporal lobe epilepsy.

Animals were randomly assigned to one of several treatment groups: SE alone (n = 16), SE + grafts (n = 12), SE + designer receptors exclusively activated by designer drugs (DREADDs) graft (n = 5), and SE + clozapine-N-oxide (n = 5). A group of 10 age-matched naive control rats was also included for comparison of behavioral and histologic results.

Electrodes were implanted into the animals in the fourth month after induced SE. One month thereafter, they were connected to a tethered video-EEG system, which continuously monitored behavior and electrographic activity.

Test animals and controls also underwent multiple tests for assessing cognitive and mood function. After completion of EEG recordings and behavioral tests, all were euthanized and their brain tissues harvested.

Seizures Reduced

Results showed that grafting hMGE cells into the hippocampus after SE reduced the frequency and severity of spontaneous recurrent seizures in the chronic phase of epilepsy by 72% (P < .0001), and reduced intense, stage V spontaneous recurrent seizures by 78% (P < .0001).

Although the average duration of individual seizures was similar between groups, the percentage of time spent in seizure activity was considerably shorter in the SE + grafts group than in the SE-only group (72% reduction; P < .0001).

Cell grafting was also effective in easing mood impairments. Using the motivation to eat as a marker of this symptom, the average latency to reach and smell food in the SE-alone group was 10-fold longer than among controls (P < .001). This implied significantly decreased motivation.

Although the latencies to reach and smell food in the SE + grafts group were significantly shorter than in the SE-alone group (P < .001), they were closer to the levels measured in controls (P > .05).

The investigators also used a sucrose preference test as a marker of depression/anhedonia, the inability to feel pleasure in activities that offer comfort in normal conditions.

Although the absence of anhedonia was evident in control animals from their strong preference to consume sucrose solution instead of water, SE-alone animals consumed sucrose solution and water in almost equal amounts. By comparison, animals who received grafts exhibited behavior comparable with that of control animals by consuming a higher amount of sucrose solution.

Interestingly, grafting also had several neuroprotective and anti-epileptogenic effects in the host hippocampus. This was evidenced by reductions in host interneuron loss, abnormal neurogenesis, and aberrant mossy fiber sprouting in the dentate gyrus.

SRS Replacement?

The results now open the door to the potential for autologous MGE-cell transplantation to reduce spontaneous recurrent seizures, the investigators note.

The "development of MGE cell therapy for patients with epilepsy has not received much traction because of the nonavailability of appropriate donor cells," they write.

By comparison, the current research allows for autologous hMGE cell grafting, which does not require long-term immune suppression after the procedure and promotes the possibility of integration between the host hippocampus and graft-derived neurons.

Nevertheless, the investigators recognize that more work needs to be done to determine the safety of the novel approach.

"We now need to test these same cells in chronic epilepsy, because there are some risks associated with transplanting them," Shetty explained.

"For one, we have to make sure that transplantation does not lead to the formation of tumors, and for that you need to do long-term studies," he said.

"Translational Value for the Clinic"

Asked to comment on the findings, Detlev Boison, PhD, director of basic and translational research at the Legacy Research Institute, Portland, Oregon, called the study a "masterpiece."

"The significance of the work is manifold," said Boison, who was not involved in the research.

"The cellular implants not only reduce seizures in epilepsy, but also suppress epileptogenesis and have robust disease-modifying effects, as assessed by improvement in behavioral comorbidities of epilepsy," he added.

Because the cells are autologous, "this approach has translational value for the clinic. However, for future clinical trials it needs to be considered that cell transplantation is still an invasive approach," Boison said.

Study coauthor Shetty noted that he's confident the findings may lead to viable treatment options for individuals suffering temporal lobe epilepsy.

"In reality, people with drug-resistant epilepsy have very few options for treatment," he said. "Cell therapy is an experimental therapy that has the potential to provide permanent seizure control, as well as improve cognitive function and mood."

The study was funded by grants from the Department of Defense, the state of Texas, the Department of Veterans Affairs, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health. Dr Shetty and Dr Boison have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online December 17, 2018. Full text

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