Gene Targeting Treatment Seen to Nearly Wipe Out Epileptic Death in Early Study in Mice

Gene Targeting Treatment Seen to Nearly Wipe Out Epileptic Death in Early Study in Mice

A single dose of Stoke Therapeutics’ antisense oligonucleotide, targeting the SCN1A gene, largely eliminated the incidence of seizures as well as sudden unexplained death in epilepsy (SUDEP) cases of mice with Dravet syndrome, a study showed.

The most recent preclinical data on Stoke’s targeted augmentation of nuclear gene output technology was presented in the poster “Targeted Augmentation of Nuclear Gene Output (Tango) of Scn1a Prevents Seizures and SUDEP in a Mouse Model of Dravet Syndrome,” at the American Epilepsy Society 2018 conference in New Orleans.

Antisense oligonucleotides (ASOs) are small RNA-targeting molecules that can promote the production of faulty or insufficient levels of proteins in several genetic diseases. This strategy takes advantage of a naturally occurring process, called RNA splicing, in which immature RNA sequences are processed by removing small bits of its sequence to generate a functional protein coding sequence.

The majority of Dravet syndrome patients carry mutations in the SCN1A gene, which provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.1.

Stoke has designed ASOs to specifically bind to SCN1A RNA sequence and support its translation into a functional NaV1.1 sodium channel.

Working in collaboration with researchers from the University of Michigan, Stoke showed through this study that its ASO can effectively target the nonproductive SCN1A sequence in both healthy mice and in a mouse model of Dravet syndrome.

Identified ASOs significantly increased the expression of SCN1A in cultured human neural-progenitor cells (those that may develop into neurons in the brain) and in differentiated neurons with no effect on the expression of other voltage-gated sodium channel genes.

A single injection of the lead ASO into the brains of mice led to a significant and dose-dependent increase of SCN1A immature RNA levels, as well as of its NaV1.1 encoded protein, without affecting other similar calcium channels.  And it effectively restored the levels of NaV1.1 protein to normal amounts in the brains of mice with Dravet syndrome.

It also dramatically cut the incidence of seizures and SUDEP events in 99% (79 of 80) of the Dravet syndrome mice. The positive effects of the treatment were sustained for approximately 13 weeks.

“These results in the Dravet mouse model using Stoke’s ASO technology have been quite remarkable,” Lori Isom, PhD, Maurice H. Seevers professor and chair of pharmacology at the University of Michigan Medical School, said in a press release. “We’re hopeful we’ll see the same results in the clinic.”

Stoke expects to advance its SCN1A targeting ASO into clinical trials soon, with the possibility of requesting regulatory approval in 2020.

“These data are particularly exciting because this approach could lead to the first disease-modifying treatment for patients with Dravet Syndrome,” said Edward M. Kaye, MD, the company’s CEO. “Stoke is also working on applying this technology to develop precision medicines for other genetic epilepsies.”

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