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Investigations injected an oligonucleotide into the brain after a status epilepticus event in an animal model and the therapy appeared to turn off expression of miRNA-134 and reduced subsequent seizures by more than 90 percent.
A specific microRNA found only in the brain — miRNA-134 — has been implicated in epilepsy both in animal models and in human tissue. Now, scientists used an antagomir, a chemically-engineered oligonucleotide, to turn off expression of miRNA-134 and found that it significantly reduced the number of seizures, as well. In fact, the silencing of miRNA-134, which is thought to control dendritic spine morphology, reduced hippocampal CA3 pyramidal neuron dendritic spine density by 21 percent and protected mice against seizures and hippocampal injury caused by status epilepticus. When the antagomir was injected into the brain after the initial status event, subsequent seizures were reduced by more than 90 percent, investigators reported in the June 10 online edition of Nature Medicine.
While the findings are only in animals, epilepsy experts say that the results are promising and provide a potential new route for drug development in patients with status epilepticus. There are no medicines currently available that protect the brain against seizures in these patients.
In the last five years, several teams have reported the upregulation of miRNAs in epilepsy and a number of other neurological disorders. That miRNA-134 regulates the structure of dendritic spines — contact points for excitatory transmission — bolstered the idea that it could play a role in seizure activity, said David C. Henshall, PhD, a senior lecturer in molecular physiology and neuroscience at the Centre for the Study of Neurological Disorders at the Royal College of Surgeons in Ireland.
Dr. Henshall and his colleagues collected tissue from temporal lobe resections from patients undergoing surgery, as well as animal models of seizure activity. They decided to silence miRNA-134 to figure out what role it was playing in the regulation of seizure activity. They used an antagomir, which binds to and removes the miRNA. According to Dr. Henshall, miRNA-134 was silenced within 24 hours of injecting an antagomir into the ventricle adjacent to the hippocampus. Once miRNA-134 was shut down, they subjected the animals to seizures and found that the mice had a 50 to 60 percent reduction in the duration and severity of seizures. The damage to the brain was also dramatically reduced by up to 90 percent.
They injected the antagomir after the initial status epilepticus and counted the number of epileptic seizures with an implantable EEG device. In this second study, there was a 92 percent reduction in subsequent seizures and some mice never had a seizure at all. They followed more mice out to around two months post-status. At this second time period, epileptic seizures were still down by 70 percent.
Dr. Henshall said that they have knocked out other miRNAs and “have not seen anything like this.” He added that they do not know how long the effect will last. There are many formidable challenges for the use in humans. Antagomirs do not cross an intact blood-brain-barrier and in these animal studies they injected it directly into the brain. They have to figure out a way to get the antagomirs to work through the periphery. The scientists are now working on a formulation using nanoparticle technology to deliver it intranasally.
They are also testing the animals to see whether silencing the miRNA has negative consequences, such as altering cognition and/or behavior. miRNA-134 is normally present in brain to regulate the size of dendritic spines, which is an index of synaptic strength.
DR. AMY BROOKS-KAYAL: “One of the issues is that only a small fraction of those who go into status epilepticus go on to develop epilepsy. We would have to define who would be the perfect person for such an intervention and you would want to find something that is non-invasive and safe. We don't know about the toxicity of antagomirs on learning and memory.”
“This is certainly a novel finding,” said Amy Brooks-Kayal, MD, chief and Ponzio Family Chair in Pediatric Neurology at Children's Hospital Colorado and professor of pediatrics, neurology and pharmaceutical sciences at the University of Colorado. “This is the first time that anyone has shown that you can modify epilepsy through the manipulation of miRNA. But this will certainly not be available anytime in the near future for patients. It has an exciting potential as a therapeutic target but there are still a lot of questions.”
“One of the issues is that only a small fraction of those who go into status epilepticus go on to develop epilepsy,” Dr. Brooks-Kayal added. “We would have to define who would be the perfect person for such an intervention and you would want to find something that is non-invasive and safe. We don't know about the toxicity of antagomirs on learning and memory.” She said that such an intervention could also be used on the heels of head injury to reduce the risk for epilepsy.
“Blocking programs of gene transcription using antagomirs to protect the brain is an exciting area of uncharted territory in epilepsy research,” said Jeffrey L. Noebels, MD, PhD, Cullen Trust for Health Care Endowed Chair and professor of neurology, neuroscience, and molecular and human genetics and vice chair for Research in the department of neurology at Baylor College of Medicine.
DR. DAVID C. HENSHALL said there are many formidable challenges for the use of the antagomirs in humans. He noted that antagomirs do not cross an intact blood-brain-barrier, and the scientists are now working on a formulation using nanoparticle technology to deliver it intranasally.
“Like other antiepileptic drugs, dose-related off-target effects and the need to rapidly deliver the correct amount to the irritated brain region remains an obstacle. Deleterious cognitive side effects of spine dysregulation might prove to be equally long lasting. However, there is little doubt that antagomirs provide a new smart warhead in the search for treatments to prevent brain damage leading to epilepsy.”
Roger P. Simon, MD, professor of neurology and neurobiology at the Morehouse School of Medicine, agreed. “This work adds to the expanding understanding of miRNAs as potent regulators of gene expression in brain. If confirmed and expanded, this miRNA approach might provide truly disease modifying therapy.”