Opportunities and challenges for microRNA-targeting therapeutics for epilepsy

Abstract

Epilepsy is a common and serious neurological disorder characterised by recurrent spontaneous seizures. Frontline pharmacotherapy includes small-molecule antiseizure drugs that typically target ion channels and neurotransmitter systems, but these fail in 30% of patients and do not prevent either the development or progression of epilepsy. An emerging therapeutic target is microRNA (miRNA), small noncoding RNAs that negatively regulate sets of proteins. Their multitargeting action offers unique advantages for certain forms of epilepsy with complex underlying pathophysiology, such as temporal lobe epilepsy (TLE). miRNA can be inhibited by designed antisense oligonucleotides (ASOs; e.g., antimiRs). Here, we outline the prospects for miRNA-based therapies. We review design considerations for nucleic acid-based approaches and the challenges and next steps in developing therapeutic miRNA-targeting molecules for epilepsy.Current versus future drugs for epilepsy: the need for change Epilepsy (see Glossary) is a common, often life-long brain disease characterised by recurrent, spontaneous seizures that are the result of hypersynchronous discharges of neurons [1]. There are more than 20 different small-molecule drugs in clinical use that reduce or prevent seizures in people with epilepsy. This is a remarkable achievement, certainly relative to the lack of treatments for many neurological disorders, and is owed to a solid mechanistic understanding of how seizures arise through imbalances between excitation and inhibition and the availability of good disease models that identify molecules with antiexcitability properties [2]. However, antiseizure drugs likely do not substantially alter the underlying pathophysiology of epilepsy, and one-third of patients are refractory to current treatments. Addressing this treatment gap is a major priority [1,3], and, increasingly, researchers are looking at substantially different targets.Acquired forms of epilepsy, such as TLE, have a limited genetic basis and probably arise from an earlier brain insult that leads to select cell loss, gliosis, neuroinflammation, and vascular and microscopic as well as macroscopic reorganisation of brain networks [4,5]. Because of this, single targets, such as ion channels, may be unsuitable or insufficient to overcome drug resistance, achieve disease modification, or prevent epileptogenesis [6] (Box 1). Novel approaches that can modify multiple targets may be necessary. Additionally, suitable target(s) may not reside on the outside of neurons but instead be intracellular. Both challenges could be solved by using RNAbased medicines such as ASOs, which offer virtually unlimited potential to target any gene, and small noncoding RNAs called microRNAs (miRNAs), which are 'multi-pathway' regulatory molecules (for a recent review on the general topic of RNA medicines, the reader is referred elsewhere [7]).The first miRNA medicine reached human trials in 2013 [8], and several others are in clinical testing. The versatility of ASO-based medicines was elegantly dem...

MicroRNA inhibition using antimiRs in acute human brain tissue sections

“…ASO mechanisms of action 41 can include steric blocking of mRNA translation, degradation of target mRNA or regulation of RNA splice events 42 . Different ASOs may also have different lengths and chemistries, which can affect their uptake, bioavailability and cellular effects 8 . Our methodology provides a platform which could be used to test all of these ASO mechanisms and properties in real human brain tissue.…”

“…One leading preclinical solution to this problem targets the microRNA (miRNA) system [8][9][10][11] . MiRNAs are endogenous ~22nt noncoding RNAs which repress the translation of targeted mRNAs via complementary binding to targets regions in the 3' UTR 12 .…”

“…MiRNAs are endogenous ~22nt noncoding RNAs which repress the translation of targeted mRNAs via complementary binding to targets regions in the 3' UTR 12 . MiRNA dysregulation is linked to epilepsy [8][9][10][11]13 and individual miRNAs may represent either biomarkers or therapeutic anti-seizure targets. Antisense oligonucleotides (ASO) targeting miRNAs, termed 'antimiRs' provide potent, specific and lasting in vivo knockdown of their targets.…”

Non-Coding RNAs: New Biomarkers and Therapeutic Targets for Temporal Lobe Epilepsy

“…However, due to the multi-targeting and multi-pathway actions of miRNAs, prediction and therapeutic function are not easy to approach. Several functional studies have shown the potential therapeutic targets of epilepsy on miRNA levels through administration of chemically engineered antisense oligonucleotides that target specific miRNAs called mimics or antagomirs, which are capable of reproducing or inhibiting specific miRNA function, respectively [ 58 ]. It emerged from data that prolonged seizures in rodents cause up-regulation of miR-134, and levels of miR-134 are also higher in the brain of patients with drug-resistant TLE.…”

Pathophysiological Mechanisms Underlying the Etiologies of Seizures and Epilepsy

“…There have been more than 300 studies on miRNA and epilepsy, and over 100 different miRNAs are altered in experimental models and human samples. Of these, there are 10-20 miRNAs that appear consistently dysregulated and for which there is functional evidence for effects on seizures (44).…”