RNA Modulation in KCNB1 Model of Lennox Gastaut Syndrome

Project: Research project

Project Details

Description

Lennox-Gastaut Syndrome (LGS) is a severe pediatric epilepsy syndrome that accounts for 1-4% of childhood
epilepsies. LGS includes a characteristic EEG pattern, some degree of cognitive impairment, and multiple
seizure types that respond poorly to available treatments. Novel therapies are needed to both better control
seizures and improve non-seizure outcomes. Up to 35% of LGS cases have no obvious cause and are presumed
to result from a genetic mutation. Heterozygous mutations in KCNB1 have been identified as a genetic cause in
some patients with LGS. In genetic disease resulting from a heterozygous mutation, the individual has one good
copy and one bad copy of the gene. A major unanswered question for KCNB1-associated LGS is whether
disease results because one good copy is not enough, or from harmful effects of the bad copy. Based on our
current understanding, we think that the bad copy exerts harmful effects and poisons residual function from the
good copy. To formally investigate this, we will use a mouse model with a Kcnb1-associated LGS mutation and
evaluate the effects of suppressing expression of the bad copy using an antisense oligonucleotide (ASO). The
ASO will promote specific degradation of RNA from the bad copy, while RNA from the good copy will be
preserved. If we see improvement in neurological and behavioral symptoms in ASO-treated Kcnb1 LGS mice, it
will provide evidence that harmful effects of the bad copy are responsible for disease. Addressing this critical
gap in our knowledge will improve our understanding of KCNB1-associated LGS and pave the way for
development of RNA-based disease modifying therapy.
StatusActive
Effective start/end date4/1/213/31/23

Funding

  • LGS Foundation (AGMT 4/7/21)

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