Opportunities and challenges for microRNA-targeting therapeutics for epilepsy. (July 2021)

• Record Type: Journal Article
• Authors: Morris, Gareth; O'Brien, Denis; Henshall, David C.
• Is Part Of: Trends in pharmacological sciences. Volume 42:Number 7(2021)
• Page Start: 605
• Page End: 616
• Publication Date: 2021-07
• Subjects: microRNA -- therapeutics -- antisense oligonucleotides -- epilepsy; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2021.04.007
• Languages: English
• ISSNs: 0165-6147

Abstract

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. Highlights: MicroRNAs are small noncoding RNAs that suppress the translation of mRNAs and have emerged as therapeutic targets in epilepsy and other diseases. Inhibition of certain miRNAs with antisense oligonucleotides (ASOs) is therapeutic in preclinical temporal lobe epilepsy (TLE) models. Chemical modifications can be made to improve the therapeutic properties of ASOs. The blood–brain barrier is an obstacle in delivering ASOs as therapies in neurological disease, and ASOs currently have to be administered by direct central injection. miRNA-targeting ASOs are in clinical trials for other diseases, raising the prospect that they could also be safely applied in epilepsy.