Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Campbell, Aoife; Morris, Gareth; Heller, Janosch P.; Langa, Elena; Brindley, Elizabeth; Worm, Jesper; Jensen, Mads A.; Miller, Meghan T.; Henshall, David C.; Reschke, Cristina R.

doi:10.1038/s41598-020-79350-7

Cited by 16 publications

(15 citation statements)

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“…We next investigated whether inhibiting miR-134 could alter key phenotypes in F1 Ube3a m−/p+ mice. Silencing was achieved using a locked nucleic acid (LNA) antimiR targeting miR-134 (Ant-134), 32 ( Figure 2 E). F1 Ube3a m−/p+ mice received a single intracerebroventricular (ICV) injection at P21 of 0.1 nmol Ant-134 or a scrambled control antimiR (Scr), and brains were extracted 24 h later, to coincide with maximal knockdown.…”

Section: Resultsmentioning

confidence: 99%

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Campbell¹,

Morris²,

Sanfeliu³

et al. 2022

Molecular Therapy - Nucleic Acids

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Section: Resultsmentioning

confidence: 99%

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Campbell¹,

Morris²,

Sanfeliu³

et al. 2022

Molecular Therapy - Nucleic Acids

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“…Preclinical studies have shown that i.c.v injection of antagomir targeting miRNA-134 protects against evoked seizures in multiple rodent models of epilepsy, including models of earlier-life seizures and neurodevelopmental disorders (Reschke et al, 2017;Gao et al, 2019;Campbell et al, 2021;Campbell et al, 2022). In the first study here, we found that suppression of miR-134 by antimiR ASOs did not affect seizure duration, severity or temperature threshold for F1.Scn1a(+/-) tm1kea mice.…”

Section: Discussionmentioning

confidence: 53%

“…Ant-134 does not change the frequency of spontaneous seizures and SUDEP in F1.Scn1a(+/-) tm1kea mice Some therapeutics may fail against hyperthermia-induced seizures but nevertheless work against spontaneous seizures and SUDEP (Hawkins et al, 2017). Previous work showed that Ant-134 when injected at 0.1 nmol reduced seizures evoked by systemic kainic acid in P21 mice (Campbell et al, 2021).…”

Section: Resultsmentioning

confidence: 96%

“…Thus, Ant-134 promotes a potent seizure reduction in adult models of evoked seizures and epilepsy (Jimenez-Mateos et al, 2012;Reschke et al, 2021). Targeting miR-134 also reduced kainic acidinduced seizures, at least within a narrow dose-range, in juvenile (P21) mice (Campbell et al, 2021). Interestingly, in a mouse model of Angelman Syndrome carrying a loss-of-function mutation in the maternally-inherited copy of the Ube3a gene, Ant-134 treatment also reduced effectively the susceptibility to audiogenically-evoked seizures (Campbell et al, 2022).…”

Section: Introductionmentioning

confidence: 96%

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Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome

Gerbatin

Augusto

Morris

et al. 2022

eNeuro

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Dravet Syndrome (DS) is a catastrophic form of paediatric epilepsy mainly caused by non-inherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalised seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short non-coding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels.Inhibiting microRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(+/-) tm1kea mice. At P17, animals were intracerebroventricular injected with 0.1 -1 nmol of Ant-134 and subject to a hyperthermia challenge at P18. A second cohort of P21 F1.Scn1a(+/-) tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wildtype and F1.Scn1a(+/-) tm1kea mice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134 treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS. 2 Significance StatementSeveral preclinical models of epilepsy have implicated miR-134 as a therapeutic target for seizure control and anti-epileptogenesis. The present study here explored whether targeting miR-134 has effects on seizures and mortality in a mouse model of Dravet Syndrome. The results indicate that suppression of miR-134 using an antimiR did not protect against hyperthermiainduced seizures, spontaneous seizures or SUDEP in F1.Scn1a(+/-) tm1kea mice.The findings suggest that miR-134 is not a therapeutic target in DS.

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“…Introduction of an miRNA manipulation would need to be performed with full knowledge of potential interactions. Our laboratory has made recent progress in this regard, observing that while the antiseizure effects of Ant-134 are retained in juvenile mice, these animals were less tolerant of higher doses [108]. Beyond this, clinical development will likely require partnering with biotechnology or pharmaceutical companies.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Opportunities and challenges for microRNA-targeting therapeutics for epilepsy

Morris

O’Brien²,

Henshall

2021

Trends in Pharmacological Sciences

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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...

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Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Cited by 16 publications

References 41 publications

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome

Opportunities and challenges for microRNA-targeting therapeutics for epilepsy

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