Human iPSC-Derived GABA-Ergic Precursor Cell Therapy for Chronic Epilepsy
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abstract
Epilepsy, a brain disorder that produces unpredictable incidences of seizures, affects both mental and physical functions. Approximately three million people in the United States have epilepsy and nearly 200,000 new cases of epilepsy are diagnosed each year. Nearly 30% of patients with epilepsy have chronic temporal lobe epilepsy, a condition characterized by the progressive expansion of seizures that arise mostly from a region in the temporal lobe of the brain called the hippocampus. As this region of the brain is important for functions such as learning, memory, and mood, epilepsy considerably affects these functions. Although it is clear that seizures are symptoms of an abnormal brain function, the underlying causes of seizures are unknown in most cases. However, an initial precipitating event such as head injury is believed to be the cause in a significant fraction of cases. Therefore, there is a growing concern that blast-related head injuries (mild to moderate traumatic brain injuries) among soldiers returning from Iraq and Afghanistan could result in epilepsy in the coming years and decades.While head injury has received considerable attention as an important cause of seizures and epilepsy, it is difficult to predict the types of injuries that cause epilepsy and the time lag (number of years) between injury and the development of epilepsy. Hence, prevention of epilepsy through prophylaxis measures is difficult to achieve and the treatment for epilepsy typically starts after the first seizure event. Currently, there is no cure for epilepsy, though lifelong intake of antiepileptic drugs ise effective for controlling seizures in nearly 50% of patients. Importantly, seizures in many patients are drug resistant. Furthermore, drug therapy has many side effects, and most patients with temporal lobe epilepsy exhibit learning and memory impairments and depression. Surgical resection of the epileptic hippocampus and surrounding regions are useful for controlling seizures in most cases of drug-resistant epilepsy; however, not all patients with drug-resistant epilepsy are eligible for such surgery because of potential adverse effects on brain function. Furthermore, hippocampal resection surgery does not cure major co-morbidities (cognitive and mood dysfunction) of temporal lobe epilepsy. Considering these, development of alternative therapies that have promise for substantially controlling seizures as well as improving functions such as learning, memory, and mood in people with chronic temporal lobe epilepsy has immense value.A type of neurons that synthesize the inhibitory neurotransmitter GABA and control the abnormal activity of other neuronal populations in the hippocampus exhibit considerable reductions in number in temporal lobe epilepsy. Hence, novel cell transplantation strategies that are efficacious for adding substantial numbers of GABA-producing inhibitory neurons into the epileptic hippocampus will likely be effective for suppressing chronic seizures. Additionally, considerable seizure-control mediated by grafted GABA-ergic neurons may also reverse other seizure-related problems such as impairments in learning and memory function and depression. From this perspective, findings in our recent study are relevant, which showed that bilateral grafting of GABA-ergic precursors derived from the fetal rat brain into the hippocampus of rats exhibiting chronic temporal lobe epilepsy suppressed spontaneous seizures as well as reversed cognitive and mood impairments. However, clinical application of such GABA-ergic cell types is not feasible because of the difficulty in obtaining the required amounts of GABA-ergic neurons from human fetal tissues and ethical issues associated with the use of human fetal tissues.Thus, there is a need to find human cell types that are not only amenable for expansion in culture but also capable of providing an unlimited supply of GABA-ergic precursor cells for clinical application. Medial ganglionic eminence-like GABA-ergic neural precursors generated from the human induced pluripotent stem cells (i.e., human skin fibroblasts reprogrammed into pluripotent stem cells through insertion of critical transcription factors) meet these criteria. A novel technology has been developed by our collaborator to obtain large amounts of GABA-ergic progenitors from human induced pluripotent stem cells. Our preliminary studies in a rat model of chronic temporal lobe epilepsy have shown promise of these cells for easing spontaneous seizures as well as for improving cognitive function. However, rigorous long-term studies using continuous electroencephalographic recordings and comprehensive behavioral analyses are needed to authenticate their efficacy for treating spontaneous seizures and other co-morbidities of temporal lobe epilepsy. Therefore, in this project, we propose to rigorously examine whether grafting of these human derived GABA-ergic cells into the epileptic hippocampus would considerably reduce spontaneous seizures on a long-term basis and reverse cognitive dysfunction and depression. These studies will employ a rat model of chronic temporal lobe epilepsy exhibiting spontaneous recurrent seizures, learning and memory impairments, and depressive-like behavior. In summary, the experiments proposed in this project have immense value for developing a clinically applicable cell therapy for chronic temporal lobe epilepsy.
