None approved; Zorevunersen (STK-001) in Phase 3
Dravet syndrome is a severe developmental epileptic encephalopathy that typically begins in the first year of life with prolonged, fever-associated seizures. It progresses to multiple seizure types, developmental regression, cognitive impairment, and motor difficulties. Most cases are caused by de novo loss-of-function mutations in the SCN1A gene, which encodes the Nav1.1 voltage-gated sodium channel alpha subunit. Nav1.1 is predominantly expressed in inhibitory GABAergic interneurons in the brain. When one copy of SCN1A is non-functional, these interneurons cannot fire properly, leading to an excitation-inhibition imbalance that manifests as epilepsy.
Dravet syndrome is a haploinsufficiency disorder — one working copy of SCN1A is not enough to produce sufficient Nav1.1 protein. This makes it amenable to a specific ASO strategy: upregulating the remaining functional allele to increase its protein output. Rather than silencing a gene or modifying splicing, the ASO targets a naturally occurring regulatory element called a poison exon in the SCN1A pre-mRNA.
Poison exons are non-productive exons that, when included in the mRNA, introduce a premature stop codon and trigger nonsense-mediated mRNA decay (NMD) — effectively destroying the transcript. By designing an ASO to block the inclusion of this poison exon, the proportion of productive SCN1A mRNA increases, and more Nav1.1 protein is produced from the one working copy. This approach is called Targeted Augmentation of Nuclear Gene Output (TANGO).
Stoke Therapeutics is developing Zorevunersen (formerly STK-001), an ASO that targets the poison exon in SCN1A. It is currently in Phase 3 clinical trials. Early clinical data showed reductions in convulsive seizure frequency in Dravet syndrome patients, with an acceptable safety profile. This is the most advanced clinical program for an upregulation ASO and represents a new therapeutic paradigm — increasing expression of a haploinsufficient gene rather than silencing a toxic one or modifying splicing.
The TANGO principle extends beyond Dravet syndrome. Many genetic diseases are caused by haploinsufficiency, where one functional gene copy produces insufficient protein. If a poison exon or other non-productive regulatory element exists in that gene’s pre-mRNA, an ASO can potentially be designed to block it and boost protein output.
Pequliar designs personalized ASO candidates for Dravet syndrome patients, targeting the SCN1A poison exon to promote productive splicing and increase Nav1.1 protein levels. Because individual patients may carry different SCN1A mutations on the non-functional allele, the sequence context around the target site can vary, and a personalized design ensures optimal binding to the specific patient’s pre-mRNA. The platform scores candidates for binding affinity, structural accessibility, and off-target safety, delivering synthesis-ready sequences suitable for preclinical evaluation.
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Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.