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

Campbell, Aoife; Morris, Gareth; Sanfeliu, Albert; Augusto, Joana; Langa, Elena; Kesavan, Jaideep; Nguyen, N.T.; Conroy, Ronán; Worm, Jesper; Kielpinski, Lukasz Jan; Jensen, Mads A.; Miller, Meghan T.; Kremer, Thomas; Reschke, Cristina R.; Henshall, David C.

doi:10.1016/j.omtn.2022.04.009

Cited by 17 publications

(14 citation statements)

References 67 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…In a paediatric model of status epilepticus in P21 mice, Ant-134 treatment derepressed cortical Dcx levels and this effect was associated with seizure suppression (Campbell et al, 2021). Similarly, in a genetic mouse model of Angelman Syndrome, the reduced susceptibility to audiogenic-evoked seizures in Ant-134-treated N4 Ube3a m-/p+ mice was associated with upregulation of Dcx (mRNA and protein) in the hippocampus and increased Creb1 protein in cortex (Campbell et al, 2022). Here, we found that scr F1.Scn1a(+/-) tm1kea mice show similar levels of miR-134 and related targets (Limk1,Creb1 and Dcx) in comparison to the scr F1.Scn1a(+/+) tm1kea group.…”

Section: Discussionmentioning

confidence: 92%

“…However, miR-134 is not upregulated in all epilepsy models, including kainic acid-induced seizures in P21 mice and elevated miR-134 was observed in the cerebellum but not hippocampus in a mouse model of the neurodevelopmental disorder Angelman syndrome (Campbell et al, 2021;Campbell et al, 2022).…”

Section: Discussionmentioning

confidence: 94%

“…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). Whether targeting miR-134 has effects in other models of genetic epilepsy is unknown, although ion channel-specific epilepsies can be treated by miRNA-targeting antimiRs in mice (Gross et al, 2016;Tiwari et al, 2019).…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…We used our method as a platform to test ant-134 in human brain tissue. We applied ant-134 for 24 h (Figure 2A,B) at a range of concentrations (based on previous work in induced pluripotent stem cells 15 ). To verify the viability of our method, we assessed RNA integrity in a subset of these samples, and compared them with equivalent neocortical samples that were transported without ACSF.…”

Section: Mirna-134 Inhibition In Human Brain Tissuementioning

confidence: 99%

MicroRNA inhibition using antimiRs in acute human brain tissue sections

et al. 2022

Self Cite

View full text Add to dashboard Cite

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 μmol L −1 and 90% reduction at 3 μmol L −1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effectsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

show abstract

The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis

Xie,

Chen,

et al. 2023

Funct Integr Genomics

View full text Add to dashboard Cite

Epilepsy is a neurological disorder that impacts millions of people worldwide, and it is characterized by the occurrence of recurrent seizures. The pathogenesis of epilepsy is complex, involving dysregulation of various genes and signaling pathways. MicroRNAs (miRNAs) are a group of small non-coding RNAs that play a vital role in the regulation of gene expression. They have been found to be involved in the pathogenesis of epilepsy, acting as key regulators of neuronal excitability and synaptic plasticity. In recent years, there has been a growing interest in exploring the miRNA regulatory network in epilepsy. This review summarizes the current knowledge of the regulatory miRNAs involved in inflammation and apoptosis in epilepsy and discusses its potential as a new avenue for developing targeted therapies for the treatment of epilepsy.

show abstract

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

Cited by 17 publications

References 67 publications

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

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

MicroRNA inhibition using antimiRs in acute human brain tissue sections

The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis

Contact Info

Product

Resources

About