An international alliance of academic and industry partners announced this week the receipt of €11.5 million ($15.4 million) in funding from the European Union to study the role of microRNAs in epilepsy, as well as to develop diagnostics and therapeutics based on the small, non-coding RNAs.
The consortium, called EpimiRNA, was created in response to a call for proposals related to consortium-based research into epilepsy under the EU's Seventh Framework Programme, according to David Henshall, a professor at the Royal College of Surgeons in Ireland and the consortium's coordinator.
With the role of miRNAs in epilepsy a long-standing research avenue in his lab, he contacted another group to discuss responding to the EU's funding opportunity, and "the consortium started to build from there," he told Gene Silencing News.
To date, there has been little research examining miRNAs in epilepsy when compared with other disease areas such as cancer. However, Henshall and colleagues last year published a key paper describing the neuroprotective and seizure-suppressive effects of miR-134 in a form of epilepsy called temporal lobe epilepsy.
Specifically, they found that silencing the brain-specific miRNA in animal models reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21 percent and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus, a state of persistent seizure.
"Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90 percent and mitigated the attendant pathological features of temporal lobe epilepsy," according to the paper, which appeared in Nature Medicine.
Buoyed by these findings, Henshall said that EpimiRNA will focus its efforts on temporal lobe epilepsy, which is the most common form of the disease in adults and typically the most difficult to treat with existing medications.
"That's not to say that what we find won't be relevant to other epilepsies, but it's quite a heterogeneous disease and [is] quite well characterized," he explained.
The exact details of the consortium's research plans over its five-year term have not been made public, although Henshall said that it has five primary objectives.
The first, he said, is to identify the changes in miRNA levels in the brain that accompany the development of epilepsy using the high-throughput RNA sequencing technique HITS-CLIP.
HITS-CLIP uses ultraviolet radiation to crosslink RNA to associated RNA-binding proteins prior to immunoprecipitation, followed by deep sequencing to identify the bound RNAs, and has previously been used to identify Argonaute-based miRNA/mRNA complexes in mouse brains and in C. elegans.
With the approach, "you really know which microRNA is doing something and not just floating around in the cell," Henshall said.
Importantly, EpimiRNA is taking a "multi-model approach" to HITS-CLIP, running studies in three different rodent models of temporal lobe epilepsy, he added. "We're going to try to use those to triangulate the core signature of the microRNA changes so that we're not just getting changes unique to a particular experimental model."
At the same time, the consortium will perform sequencing experiments in tissue from epilepsy suffers, which is readily available since drug-resistant patients are often operated on to remove the part of the brain responsible for seizures.
The consortium will also investigate epilepsy-related miRNA signatures in the blood of patients and animal models to explore their diagnostic potential.
"A number of microRNAs are expressed exclusively in the brain, and their presence within the circulation would probably be a good indication that a brain injury had occurred," Henshall said, noting that epileptic seizures are known to disrupt the blood-brain barrier. Additionally, blood-based miRNA signatures could also prove useful in identifying patients who will respond to different treatments.
EpimiRNA's third goal will be to examine differences in miRNAs in a large cohort of epilepsy patients "to see if there is variation in the sequences … [that] might mean one [miRNA] isn't working properly or is targeting something it wouldn't normally target," he said.
A subset of consortium members will also apply systems biology and bioinformatics approaches to organize and analyze the data coming out of the other three efforts.
The final objective of EpimiRNA is to explore the potential of miRNA-based therapeutics for temporal lobe epilepsy.
Henshall said that much of the initial work will be on single-stranded RNA-based antagonists, such as the ones being developed by Santaris Pharma and Regulus Therapeutics for hepatitis C, but that the consortium has plans to look into "some more novel approaches."
For example, one alternative therapeutic strategy involves assaying novel chemical libraries to identify small molecules that can modulate the function of specific miRNAs, he said.
In addition to Henshall and consortium co-coordinator Felix Rosenow from Philipps University Marburg, EpimiRNA includes Royal College of Surgeons researchers Jochen Prehn, Gianpierro Cavalleri, and Norman Delanty.
Also part of the consortium are Gerhard Schratt, Carsten Culmsee, Rainer Schwarting,and Karl Klein from Philipps University Marburg; Jeroen Pasterkamp from the University Medical Center Utrecht; Stephanie Schorge from University College London; Paolo Fabene from the University of Verona; Hajo Hamer from the University of Erlangen-Nuernberg; and Duke University's David Goldstein.
Other academic members include Iscia Lopes-Cendes of the University of Campinas; Jorgen Kjems at Aarhus University; and Jens Andersen at the University of Southern Denmark.
Industrial partners include DIXI Microtechniques, Cerbomed GmbH, InteRNA Technologies, Bicoll, BC Platforms, and GABO:mi.
Henshall noted that the terms of the consortium provide industry members with access to intellectual property generated through the research, as well as certain rights to license inventions and discoveries for commercialization.