Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A Rescues Parvalbumin Interneuron Excitability and Reduces Seizures in a Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a+/− × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

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Adolescent behavioral abnormalities in a Scn1a+/− mouse model of Dravet syndrome

Epilepsy & Behavior ◽

10.1016/j.yebeh.2019.106842 ◽

2020 ◽

Vol 103 ◽

pp. 106842

Author(s):

Dilara Bahceci ◽

Lyndsey Leigh Anderson ◽

Cassandra Veronica Occelli Hanbury Brown ◽

Cilla Zhou ◽

Jonathon Carl Arnold

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Behavioral Abnormalities

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Metabolomic signature of the Dravet syndrome: A genetic mouse model study

Epilepsia ◽

10.1111/epi.16976 ◽

2021 ◽

Author(s):

Nina Miljanovic ◽

Roelof Maarten van Dijk ◽

Verena Buchecker ◽

Heidrun Potschka

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Genetic Mouse Model ◽

Model Study

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Potentiating α 2 subunit containing perisomatic GABA A receptors protects against seizures in a mouse model of Dravet syndrome

The Journal of Physiology ◽

10.1113/jp277651 ◽

2019 ◽

Vol 597 (16) ◽

pp. 4293-4307 ◽

Cited By ~ 6

Author(s):

Toshihiro Nomura ◽

Nicole A. Hawkins ◽

Jennifer A. Kearney ◽

Alfred L. George ◽

Anis Contractor

Keyword(s):

Mouse Model ◽

Dravet Syndrome ◽

Gaba A

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The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

Frontiers in Pharmacology ◽

10.3389/fphar.2021.675128 ◽

2021 ◽

Vol 12 ◽

Author(s):

Vaishali Satpute Janve ◽

Lyndsey L. Anderson ◽

Dilara Bahceci ◽

Nicole A. Hawkins ◽

Jennifer A. Kearney ◽

...

Keyword(s):

Mouse Model ◽

Drug Target ◽

Genetic Modifier ◽

Anticonvulsant Drug ◽

Dravet Syndrome ◽

Seizure Threshold ◽

Drug Resistant ◽

Spontaneous Seizures ◽

Temperature Thresholds ◽

Seizure Models

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a+/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−; Trpv1+/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.

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A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa306 ◽

2020 ◽

Author(s):

Li Gao ◽

Min Wang ◽

Linfeng Liao ◽

Na Gou ◽

Piao Xu ◽

...

Keyword(s):

Mouse Model ◽

Mitochondrial Dysfunction ◽

Nuclear Gene ◽

Redox System ◽

Premature Aging ◽

Motor Deficit ◽

Mitochondria Dysfunction ◽

Respiratory Chain Enzyme ◽

Knock Out ◽

Mtdna Mutations

Abstract The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

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