All our knowledge begins with the antisenses

Abstract

Epilepsy is the neurological disorder defined by spontaneous recurrent seizures, which are abnormal patterns of electrical discharge in the brain. A major advance in neurology over the last 20 years is the identification of genetic variation as an important cause of epilepsy, and in particular as a cause of the epileptic encephalopathies, defined by childhood-onset, treatment-resistant epilepsy accompanied by developmental delay leading to intellectual disability. Unfortunately, this progress in genetic diagnosis has yet to translate to effective precision or targeted therapeutics. However, in this issue of the JCI, Li and Jancovski et al. use antisense oligonucleotides (ASO) to treat or prevent epilepsy and epilepsy-associated cognitive and behavioral comorbidities in a mouse model of SCN2A encephalopathy, paralogous to the recurrent human variant SCN2A c.5645G>A (p.R1882Q) associated with epileptic encephalopathy. These findings may inform the development of targeted or personalized therapies for what is currently an incurable and largely untreatable disorder.

Figure 1. Antisense oligonucleotide strategies for therapeutic targeting of mRNA transcripts.

(A) Schematic showing the basic gapmer ASO approach taken by Li and Jancovski et al. (20) to target Scn2a in an experimental mouse model of SCN2A encephalopathy. (B) A splice-modifying ASO as in nusinersen (Spinraza), which alters the pre-mRNA splicing of SMN2 to facilitate integration of exon 7 into the mRNA to produce functional full-length protein. (C) miRNA-targeting ASO prevents miRNAs of interest from binding to a given RNA.