Epilepsy faces new foe in miRNAs

UTRECHT, The Netherlands—Targeted toward developing novel microRNA-based drug candidates for the treatment of complex diseases, InteRNA Technologies—in collaboration with University Medical Center (UMC) Utrecht—have released preclinical evidence showing that down-regulation of miR-135a levels can reduce seizure activity after the onset of spontaneous recurrent seizures (SRS) in chronic-stage mesial temporal lobe epilepsy (mTLE) in mouse models. The results of this research were published in the April 23, 2019, issue of the Journal of Neuroscience in a paper titled “Antagonizing increased miR-135a levels at the chronic stage of experimental TLE reduces spontaneous recurrent seizures.”

The data support the overall potential of miRNAs as a treatment modality in complex diseases, and underscore InteRNA’s expertise in the application of miRNAs as a new therapeutic approach.

The journal article demonstrates that the modulation of miR-135a levels can reduce seizures in mTLE models and identify other downstream targets that might be involved in the pathomechanism of TLE, which is poorly understood.

Among the preclinical findings, research showed for the first time that miR-135a is overexpressed in human mTLE samples and that silencing of this specific miRNA in mouse models drastically reduces the number, severity and time spent in seizures in the SRS stage, an advanced disease stage where current treatments have failed. Furthermore, novel neuronal downstream targets of miR-135a were identified, showing Mef2a, an activity-dependent transcription factor regulating synaptic strength. This is required for miR135a-induced dendritic spine changes in neurons that might induce synaptic defects involved in the pathomechanisms of TLE.

The data also indicate that targeting epilepsy-associated miRNAs opens the door to an innovative approach to treating and understanding epilepsy.

“TLE accounts for a third of all epilepsies, and available treatments lack disease-modifying effects and are ineffective in one-third of all mTLE patients,” notes Prof. Jeroen Pasterkamp of the Department of Translational Neuroscience at the UMC Utrecht Brain Center. “The data from this study indicate that targeting epilepsy-associated miRNAs has the potential to unlock a novel therapeutic entity and provides key insights into the disease biology of epilepsy.”

Roel Schaapveld, CEO of InteRNA, says, “The published data provide evidence that targeting a single miRNA could represent a new modality in the epilepsy field, where current treatments are solely based on ion channel blockers that only relieve symptoms rather than provide curative effects. We are encouraged by the results of this study that further validate InteRNA’s proprietary miRNA platform, which has the potential to target cancer, our primary focus, as well as other complex disease states outside of the realm of oncology.”

This research breakthrough is remarkable, adds Schaapveld, “as it provides evidence for the possibility for a new treatment option for chronically ill patients since to date, seizures can only be symptomatically relieved in earlier disease stages. Furthermore, the findings provide novel insights in the so-far poorly understood mechanism of mTLE by demonstrating significant involvement of miR-135a in seizure pathobiology and identifying novel downstream targets that are likely involved in neuronal defects that might cause the seizures. It is early-stage research, but exciting.”
InteRNA’s lead program, INT-1B3, “is a more advanced example in cancer of what microRNAs have the potential to do,” he says. “This program has demonstrated strong anti-tumor efficacy, reduction of metastases and activation of long-term immunity together with a good safety and tolerability profile in preclinical studies.”

According to Schaapveld, the company’s program in epilepsy is an earlier-staged demonstration of the same concept, and also highlights the ability of InteRNA’s proprietary microRNA platform to design and produce these kinds of treatment candidates within the microRNA modality.

“It was already shown that there are microRNAs involved in epilepsy, but in this publication, it is the first time that it was demonstrated that silencing of a single microRNA can drastically reduce seizures in a chronic stage of epilepsy by targeting the underlying signaling pathways,” Schaapveld says. “These findings highlight the great potential of microRNAs in the treatment of mTLE and possibly other forms of epilepsy.”

Within the last couple of years, he noted, a lot of progress has been made in the field of microRNA therapeutics as technologies have advanced and novel solutions for challenges like the delivery and stabilization of RNA-molecules in the body have been identified, adding: “The latter were problems that InteRNA has successfully addressed by applying our knowledge of miRNA biology in combination with state-of-the-art technologies.”

The microRNA approaches “offer the benefit to address a variety of targets within a specific and/or across several disease-associated pathways with one therapeutic,” Schaapveld says. “This provides a great potential for microRNAs to emerge as a new class of drugs for mono-therapeutic treatment of complex, multifaceted diseases such as cancer or CNS diseases, where current treatment options fail to deliver durable responses. Furthermore, microRNA-based therapeutics offer additional advantages such as a high level of flexibility and customization, as well as fast and cost-effective production.”