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A new arrow in the treatment quiver
DURHAM, N.C.—Epilepsy, a neurological disorder in which abnormal electrical activity in brain cells results in seizures, is the fourth most common neurological disorder, according to the Epilepsy Foundation. Some 65 million people are affected worldwide, the foundation estimates, and as with most disorders, researchers are on the hunt for new and better treatments.
In a recent STEM CELLS Translational Medicine (SCTM) paper, “Genome editing in neuroepithelial stem cells to generate human neurons with high adenosine-releasing capacity,” scientists have identified a new population of stem cells that could increase adenosine levels to help control epileptic seizures. The research team consisted of scientists at the University of Bonn and the Central Institute of Mental Health (CIMH) in Mannheim.
As reported in the SCTM paper, “The purine nucleoside adenosine has essential roles in many biochemical processes of the human body such as energy homeostasis or signal transduction. Under stress conditions, adenosine is upregulated, a response that can have extensive protective effects in various organs, including the cardiovascular, gastrointestinal, renal, muscular or immune system. In the central nervous system (CNS), high neuronal activity elicits an increase in adenosine release, which acts via A1 receptors inhibiting the release probability of presynaptic glutamate and activating postsynaptic G protein‐coupled inwardly rectifying potassium (GIRK) channels, thereby eliciting postsynaptic hyperpolarization. These responses attenuate excessive neuronal activity, thereby protecting against several pathological conditions such as ischemic injuries, trauma, reduced oxygen supply, pain and in particular, epileptic seizures.”
“Acute noxes such as cerebral ischemia have been associated with an increase in adenosine. However, this increase is not sufficient to cause, e.g., dampening of seizure activity,” Dr. Oliver Brüstle of the Institute of Reconstructive Neurobiology at the University of Bonn tells DDNews. “Our concept aims at augmenting the adenosine response and uses its anti-excitatory role to dampen epileptic activity.”
When adenosine homeostasis is altered, the authors add, it’s often associated with diseases such as epilepsy, schizophrenia or depression. High levels of adenosine are released in the face of CNS injury. Like many promising compounds, however, there are some obstacles to overcome in terms of therapeutic administration.
“Attempts to systemically deliver adenosine to needed areas in the CNS during a crisis have been hampered by adenosine’s fast metabolic breakdown, the inability to sufficiently permeate the blood-brain-barrier and serious side effects of such cardiac suppression,” explained Dr. Philipp Koch of the Hector Institute for Translational Brain Research at the CIMH. Koch led the SCTM study, together with Dr. Oliver Brüstle.
Adenosine deaminase (ADA) and adenosine kinase (ADK) are largely the two enzymes that metabolize adenosine, with ADK as the primary culprit in adenosine’s rapid metabolic breakdown. As such, the team decided to try developing cells deficient in ADK, and successfully generated cell populations with potent neuroprotective properties. In mouse models, the ADK-deficient cells—engineered from mesenchymal stem cells (MSCs)—resulted in a 35-percent decrease in epileptic seizures. The downside was that the ADK-deficient cells were non-neuronal cells, being derived from hamster kidneys, and survival time was limited.
Given those shortcomings, Koch, Brüstle and their colleagues next looked at developing neural progenitors derived from ADK-deficient stem cells from mice embryos. As per the paper, they found that zinc finger nuclease-mediated gene disruption “can be directly applied to lt-NES cells to generate ADK-deficient human neural cells.” When they tested this new cell population, they found the cells also delayed the development of epilepsy, with superiority compared to the non-neuronal cells.
“In this context we described a population of hESC-derived, long-term self-renewing neuroepithelial stem cells (lt-NES). Similar to pluripotent stem cells, this population exhibits strong self-renewal capacity enabling genetic modification, subsequent clonal selection and expansion at a scale sufficient for potential therapy,” Koch explained.
“Such stable intermediate cell populations are an attractive source for potential future cell-based therapies,” Brüstle commented. “Transplanted into the CNS, they show excellent long-term survival and functional integration without the risk of forming tumors.”
In addition, he adds that “Our long-term self-renewing neuroepithelial stem cells represent a very standardized population suitable for a number of biomedical applications. In the past, they have been successfully used for modeling neurodegenerative diseases in vitro (Koch et al., Nature 2011 and related papers) and neural transplantation (Doerr et al., Nature Communications 2017 and related publications). They are also a very useful tool for generating neurons and glia for compound development and screening applications.”
Moving forward, Brüstle says the next likely step will be to “introduce these cells into animal models of epilepsy and other neural defects.”