Disease-Modifying Treatment for Dravet Syndrome on the Horizon
A potentially disease-modifying therapy for Dravet syndrome (DS) being developed by Stoke Therapeutics (Bedford, MA) uses targeted augmentation of nuclear gene output (TANGO) to address the genetic cause of DS—a mutation in the gene encoding the Nav 1.1. sodium channel. It is hoped that not only seizure occurrence but also the symptoms of intellectual disability will be positively affected by this treatment.
For autosomal dominant diseases caused by a single gene, in which the person affected has at least 1 normal copy of the gene, TANGO upregulates production of the normal gene product. This is achieved by delivering an antisense oligonucleotide (ASO) that skips out a retained intron or other noncoding region that, if transcribed, can prevent the RNA transcript from being translated into a protein. In this way, TANGO uses the normal protein manufacturing process of the cell to increase the amount of normal RNA reaching the cytoplasm. More normal RNA transcript is translated into normal protein as a result. Because TANGO affects the amount of the normal transcript leaving the nucleus, it is active only in cells that normally express the protein in question, again using the cell's own machinery as therapy. Unlike gene therapy, there is no need to get a very large completely functional gene into the nucleus, which is important because most of the genes known to cause epilepsy are relatively large. The therapy is delivered via intrathecal injection of the ASO in buffered saline, and preclinical data suggest that the ASO remains in cells of the nervous system for 4 to 6 months, which could mean only 3 injections per year might be needed
"Our goal is to follow the natural cell machinery as closely as possible and we see the TANGO technology and upregulating sodium channels as a high-tech way to hijack the cell’s own machinery to create a therapeutic effect,” said Edward M. Kaye, MD, CEO of Stoke Therapeutics. He also noted that the company is targeting diseases in which there is a strong scientific understanding of an autosomal dominant causes including other epilepsies, congenital blindness, and autosomal-dominant hearing loss.
Data from these preclinical studies is expected to be presented at the American Epilepsy Society meeting in New Orleans November 30-Dec 4 2018. Stoke hopes to do primate and toxicology studies in 2019 with a goal of beginning clinical trials in 2020.