GABAergic signaling promotes early-life seizures in epileptic SYNGAP1<sup>+/-</sup>mice

Sullivan, Brennan J.; Kipnis, Pavel A.; Ammanuel, Simon; Kadam, Shilpa D.

doi:10.1101/2020.11.14.381749

Cited by 2 publications

(1 citation statement)

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“…Many of the initial proof-of-principle experiments to test the ability of an ASO to restore physiological protein levels can be performed in cellular models, while the efficacy of ASOs to rescue phenotypes (e.g., seizures) are, at present, constrained to animal models. These preclinical studies have been performed in SCN1A haploinsufficient cell and rodent models, and for other DEEs, there are indeed rodent models that recapitulate the phenotypes seen in humans, for instance, the Scn8a R1872W/+ mouse, which recapitulates early seizure onset and susceptibility to sudden unexpected death in epilepsy via a GOF mechanism, as well as the Syngap1 +/− mouse, which recapitulates early-life recurrent seizures that proceed into adulthood via a LOF mechanism [26, 27]. For others, including CHD2 , rodent models do not have seizures, though they do have learning and memory deficits [28].…”

Section: Models For Testing Efficacy Of Future Asos: Mouse Models and Ipscsmentioning

confidence: 99%

Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

2021

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Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

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Section: Models For Testing Efficacy Of Future Asos: Mouse Models and Ipscsmentioning

confidence: 99%