Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model

Li, Melody; Jancovski, Nikola; Jafar‐Nejad, Paymaan; Burbano, Lisseth; Rollo, Ben; Richards, Kay; Drew, Lisa; Sedo, Alicia; Heighway, Jacqueline; Pachernegg, Svenja; Soriano, Armand; Jia, Linghan; Blackburn, Todd; Roberts, Blaine R.; Nemiroff, Alex; Dalby, Kelley; Maljevic, Snezana; Reid, Christopher A.; Rigo, Frank; Petrou, Steven

doi:10.1172/jci152079

Cited by 46 publications

(53 citation statements)

References 42 publications

(57 reference statements)

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“…For example, ASO gapmers have been used in a mouse model of a genetic channelopathy that leads to epilepsy. 17 Current challenges for ASO translation from animal models to human applications include on-and off-target toxicity effects, 18 which may be unique to the human brain and not possible to observe in mice. ASO mechanisms of action can include steric blocking of mRNA translation, degradation of target mRNA, or regulation of RNA splice events.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA inhibition using antimiRs in acute human brain tissue sections

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

MicroRNA inhibition using antimiRs in acute human brain tissue sections

et al. 2022

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“…Due to their relative ease of delivery and ability to readily target widespread brain structures, ASOs are emerging as a key approach to treating epilepsies – particularly those arising from gene mutations that thus effect the whole brain – and other neurological diseases. For example, ASO gapmers, which typically favour target mRNA degradation, have been used in a mouse model of a genetic channelopathy which leads to epilepsy 40 . Current challenges for ASO translation from animal models to human clinical applications include on- and off-target toxicity effects 41 , which may be unique to the human brain and not possible to observe in mice.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA inhibition using antimiRs in acute human brain tissue sections

Morris

Langa

Fearon

et al. 2022

Preprint

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Introduction: An emerging pre-clinical approach for the treatment of pharmacoresistant epilepsy is targeting the microRNA (miRNA) system. MiRNAs are short noncoding RNAs that suppress gene expression at the post-transcriptional level. Targeting miRNAs, which is possible using antisense oligonucleotide antimiRs can produce broad effects on gene expression suited to the complex pathophysiology in temporal lobe epilepsy. Potent anti-seizure and disease-modifying effects have been reported for antimiRs targeting microRNA-134 (antimiR-134). To date, however, pre-clinical testing has been performed using in vitro cell cultures and rodent models. It is uncertain how well this approach will translate to the clinic. Here, we develop an antimiR testing platform in human brain tissue sections. Methodology: Human brain specimens were obtained with consent from patients undergoing resective surgery to treat focal drug-resistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF), dissected for clinical neuropathological examination, and unused material transferred for sectioning. Individual tissue sections were incubated in oxygenated ACSF, containing either antimiR-134 or a non-targeting control antimiR, for 24 hours at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels measured using RT-qPCR. Results: ACSF transport had no obvious impact on any clinical neurosurgical or neuropathological procedure and specimens were confirmed to be viable following this process. RNA was well-preserved by transportation of specimens in ACSF, with RNA integrity scores significantly higher than tissue transported without ACSF. AntimiR-134 mediated a specific and dose-dependent knockdown of miR-134 in human neocortical sections, with approximately 75% reduction of miR-134 at 1 μM and 90% reduction at 3 μM. These doses did not have off-target effects on expression of a selection of three other miRNAs (miR-10, miR-129 or miR-132). Significance: This is the first demonstration of antimiR-134 effects in live human brain tissues. The findings lend further support to the preclinical development of miR-134 and offer a flexible platform for the pre-clinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain.

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“…Overall, these findings suggest that reduction of SCN2A to more than haploinsufficiency could be needed to induce severe phenotypes. A knock-in mouse model of the recurrent GOF mutation R1882Q has been generated (246) showing that heterozygous mice display hyperexcitability of cortical pyramidal neurons, and develop spontaneous seizures at P1 and premature death between P13 and P30. Interestingly, reduction of Na V 1.2 expression by specific antisense oligonucleotides reduced seizures and extended lifespan.…”

Section: Na V 12 Channels (Scn2a)mentioning

confidence: 99%

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Guerrini

Conti

Mantegazza

et al. 2023

Physiological Reviews

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Developmental and epileptic encephalopathies are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures, EEG abnormalities, on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both non-genetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs, of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.

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Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model

Cited by 46 publications

References 42 publications

MicroRNA inhibition using antimiRs in acute human brain tissue sections

MicroRNA inhibition using antimiRs in acute human brain tissue sections

MicroRNA inhibition using antimiRs in acute human brain tissue sections

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

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