Science Sub-Journal: Increased SCN1A expression with antisant oligonucleotides is expected to treat Dravet syndrome.

August 31, 2020 /--- In a new study, a promising experimental new treatment appears to alter the progression of devastating diseases in mouse models of Dravet syndrome.
findings could eventually give hope to children and their parents with the disease.
study was published in the August 26, 2020 issue of the Journal of Science Translational, under the title "Antisense oligonucleotides increase Scn1a expression and reduces and SUDEP Risks in a mouse model of Dravet syndrome."
photo from Science, 2020, doi:10.1126/scitranslmed.aaz6100.
Dravet syndrome is a debilitating genetic disorder that causes stubborn seizures and can lead to sudden death.
Lori Isom, dean of the Department of Pharmacology at the University of Michigan, and her team spent years tracking the path of Drvet syndrome.
mutations in patients with Dravet syndrome cause a drop in a key protein level that normal brain cells use to control the flow of sodium ions into cells.
neurons use these sodium channels to transmit signals back and forth.
Sodium channel gene SCN1A mutates in patients with Dravt syndrome, usually resulting in only half of the amount of the corresponding functional protein Nav1.1 expressed in the brain.
SCN1A in the brain is only 50 percent expressive, and there is a high risk of severe epilepsy and sudden death," said Isom, who is not involved in the study.
" Isom team aims to use antisense oligonucleotides (ASOs) developed by biotech company Stoke Therapeutics to increase the expression of the gene in neurons to 100 percent.
in collaboration with Stoke, the Isom team tested an antonym oligonucleotide called STK-001 in a mouse model of Dravet syndrome.
Isom explains, "The brain often uses a part of the gene called a harmful exon to increase or decrease the expression of a particular gene, which is an internal regulatory mechanism.
we are using harmful exons in SCN1A to increase their expression.
" is reversible, unlike using CRISPR, viruses, or other forms of gene editing.
" gene therapy is that you permanently change something, which is risky, especially for the brain.
if you make a mistake, there's no turning back.
" Injected STK-001 into the brains of mice that carried only a healthy copy of the SCN1A gene two days after birth, 97 percent of the mice survived for 90 days, while the untreated mice had only a 23 percent survival rate at the same time.
idea is that early intervention in mice with ASO may change the brain's excitability, " says Isom, a 40-year-old.
the same is true for children with Dravet... That would be incredible.
based on encouraging results from this mouse study, Stoke recently launched a clinical study to evaluate the use of STK-001 in children and adolescents with Dravet syndrome.
the mouse study could have broader implications for treating the genetic causes of full-on epilepsy, especially in one-third of patients who have epilepsy that cannot be controlled by traditional drugs,
Isom said.
"We just need to start over and think about epilepsy from a new perspective--- starting with the genetic source, rather than passively trying to treat what has happened," he said.
" (bioon.com) Reference: 1. Zhou Han et al. Antisense oligonucleotides increase Scn1a expression and reduce rescapleps and SUDEP senses in a mouse model of Dravet syndrome. Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aaz6100.2.Investigational newrapy prevents onset of Dravet syndromes in mice.