Dravet syndrome and precision medicine

Sullivan J, Wirrell EC. Dravet Syndrome as an Example of Precision Medicine in Epilepsy. Epilepsy Currents. 2023;23(1):4-7. doi:10.1177/15357597221106281

Abstract

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development.

From the article:

Overview

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy that typically presents in the first year of life with prolonged febrile and afebrile, focal (usually hemiclonic) and generalized tonic-clonic seizures. Development is normal at onset but then slows and global delays are usually evident by 2-3 years of age. Other significant comorbidities emerge with time including crouch gait, parkinsonian features, autistic features, attention deficit disorder, growth delay and feeding problems, dysautonomia and sleep problems. The risk of sudden unexpected death in epilepsy (SUDEP) is significantly increased with a reported rate of 9.32 per 1000 person years.

Over 85% of cases are found to have , mostly de novo, pathogenic, loss-of-function SCN1A variants which result in haploinsufficiency of Nav1.1, the alpha-1 subunit of the sodium channel. Both the underlying channelopathy and the recurrent severe seizures contribute to the presence and severity of comorbidities. In a prospective study of 67 children with DS, 15 of whom were studied longitudinally, Nabbout et al found no correlation between epilepsy variables and developmental/intelligence quotient at last evaluation, but noted that those with a documented SCN1A variant exhibited greater delays than those without variants. This work suggests that the SCN1A variant significantly contributes to the encephalopathy. Conversely, other studies have reported that earlier use of appropriate therapies, or avoidance of therapies that exacerbate seizures may improve outcomes. Since 2018, there have been 3 new antiseizure medications approved for seizures associated with Dravet syndrome...

Pharmaceutical Grade Cannabidiol

Pharmaceutical-grade cannabidiol was approved by the FDA in June 2018 for the treatment of seizures associated with DS. Its exact mechanism of action is unknown – it does not significantly activate CB1 or 2 receptors, but rather may enhance neuronal inhibition (through GABAergic channels), modulate intracellular calcium (TRPV, GPR-55 or VDAC) and have an antiinflammatory effect (adenosine)...

Despite improvements in convulsive seizure frequency, no significant benefits were seen on the Quality of Life in Childhood Epilepsy or Vineland Adaptive Behavior Scales comparing cannabidiol and placebo.

Stiripentol

In 2000, stiripentol was the first medication to be specifically studied in a small cohort of DS patients where 71% of patients receiving stiripentol had a 50% or greater reduction in generalized tonic-clonic or clonic seizures compared to only 5% of those who received placebo. Impressively, 9 of the 21 who received stiripentol were seizure free during the 2-month treatment period compared to no patients who received placebo. All patients in this study were also on concomitant valproate and clobazam. There are several potential mechanisms of action including direct enhancement of inhibitory GABAergic neurotransmission in addition to inhibiting the CYP1A2, 3A4 and 2C19 metabolism of concomitant anti-seizure medications.

Fenfluramine

A post-hoc analysis of patients who enrolled in the various fenfluramine trials and received at least 1-year of treatment in the open-label extension study was done to evaluate for clinically meaningful changes on the Behavior Rating Inventory of Executive Function. In the 58 children included in this analysis, 45 (78%) achieved a greater than 50% reduction in seizures and there was clinically meaningful improvement both the emotional regulation index and the cognitive regulation index. These findings support the notion that non-seizure outcomes can improve in this patient population and allows for redefining our treatment goals as we strive to treat all aspects of the syndrome...

Other Agents in Clinical Trials

Additional mechanisms are also being explored with various agents in different stages of clinical trials including soticlestat (a cholesterol 24-hydroxylase inhibitor), as well as clemizole and lorcaserin both of which like fenfluramine, act via the serotonin pathway.

Antisense Oligonucleotide Therapy

The SCN1A gene contains a nonsense-mediated decay exon that is used to regulate the SCN1A transcript and Nav1.1 protein production. If the mRNA transcript contains this exon, it degrades and thus protein is not produced. Targeted augmentation of nuclear gene output (TANGO) technology can target these nonproductive alternative splicing events to decrease nonproductive mRNA and thus boost protein production. As this therapy targets the underlying pathogenesis, it carries the potential benefit to not only reduce seizures, but also attenuate or prevent comorbidities including SUDEP.

STK-001 is an antisense oligonucleotide (ASO), currently in clinical trials, which utilizes TANGO technology to boost Nav1.1 protein expression... 

AAV-9 Based Gene Therapy

Another novel, potential one-time disease-modifying approach to address the underlying Nav1.1 haploinsufficiency is being developed by Encoded Therapeutics. ETX-101 is an AAV-9 delivered gene therapy that expresses an engineered transcription factor under the control of a GABA-ergic cell-selective regulatory element which is designed to promote increased transcription and therefore translation of the SCN1A gene in inhibitory interneurons...

Conclusion

Making an accurate diagnosis of an epilepsy syndrome such as Dravet syndrome has allowed for the study of novel compounds and data to inform syndrome specific treatments. While this may not necessarily be a true precision medicine approach as some of the ASMs that have been approved for the treatment of seizures associated with Dravet syndrome have also demonstrated efficacy in other epilepsy syndromes, having efficacy and safety data does allow for a more systematic treatment approach for these patients.27 Having the precise understanding of the underlying genetic etiology of Dravet syndrome has paved the way for development of true precision medicine approaches. If effective, these could change the overall natural history of the syndrome as we know it and lead to improvement in domains beyond just seizures, thereby further improving the overall outcomes and quality of lives for these patients and their families.