Dravet Syndrome: Novel Approaches for the Most Common Genetic Epilepsy

Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that is mainly associated with variants in SCN1A. While drug-resistant epilepsy is the most notable feature of this syndrome, numerous symptoms are present that have significant impact on patients' quality of life. In spite of novel, third-generation anti-seizure treatment options becoming available over the last several years, seizure freedom is often not attained and non-seizure symptoms remain. Precision medicine now offers realistic hope for seizure freedom in DS patients, with several approaches demonstrating preclinical success. Therapeutic approaches such as antisense oligonucleotides (ASO) and adeno-associated virus (AAV)-delivered gene modulation have expanded the potential treatment options for DS, with some of these approaches now transitioning to clinical trials. Several of these treatments may risk the exacerbation of gain-of-function variants and may not be reversible, therefore emphasizing the need for functional testing of new pathogenic variants. The current absence of treatments that address the overall disease, in addition to seizures, exposes the urgent need for reliable, valid measures of the entire complement of symptoms as outcome measures to truly know the impact of treatments on DS. Additionally, with so many treatment options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.

CRISPR activation rescues abnormalities in SCN2A haploinsufficiency-associated autism spectrum disorder

“…Heightened levels of Scn2a mRNA did not correspond to elevated intrinsic or network neuronal hyperexcitability, nor did they lead to any change in seizure burden in naïve or convulsant-treated mice. We speculate that this could be due to a potential ceiling on total Na V 1.2 membrane density, perhaps imposed by ancillary subunits or scaffolding partners whose expression remains unchanged (Colasante et al, 2020; Hull and Isom, 2018; Isom and Knupp, 2021). Furthermore, we observed no expression or electrophysiological effects that would indicate that CRT altered the expression of other CNS sodium channel genes within the Scn2a TAD region ( Scn1a, Scn3a ) or in other sodium channels expressed in pyramidal cells ( Scn8a , which is critical for AP threshold).…”

Phenotypic and Genotypic Characteristics of SCN1A Associated Seizure Diseases

“…Another gene therapy focuses on adeno-associated virus (AAV)-delivered gene modulation. For example, an adeno-associated virus serotype 9 (AAV9) vector-based, GABAergic neuron-selective, which can upregulate endogenous SCN1A gene expression to prevent GABAergic neurons disinhibition ( Isom and Knupp, 2021 ). The treatments of genetic epilepsy will no longer be solely symptomatic to control seizures, but will be transformed into genomics-driven personalized therapy for underlying molecular defects or its consequences.…”

New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment

“…The ketogenic diet (KD) used to treat glucose transporter 1 (GLUT1) deficiency syndrome is probably the best example of PM applied to epilepsy. In GLUT1 patients the uptake of glucose into the brain is impaired because of the SLC2A1 mutation, hence, the KD provides neurons with an alternative source of energy, compensating for the consequences of the metabolic defect ( 8 ). Another clear application of a PM-based approach is the avoidance of those drugs which may cause worsening of seizures by exasperating the underlying molecular defect, i.e., sodium channel blockers must be avoided in patients with Dravet syndrome (DS) carrying loss-of-function mutations in the sodium voltage-gated channel alpha subunit 1 ( SCN1A ).…”

“…Another clear application of a PM-based approach is the avoidance of those drugs which may cause worsening of seizures by exasperating the underlying molecular defect, i.e., sodium channel blockers must be avoided in patients with Dravet syndrome (DS) carrying loss-of-function mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A). Another one is memantine for the treatment of GRIN-related disorders due to gain-of-function mutations in the NMDA receptor (8)(9)(10)(11) or quinidine and retigabine for epilepsies caused by potassium channels genes mutations (KCNT1 and KCNQ2) (6,12). In epileptic encephalopathies (EE), it would be also of interest to investigate the effect of a PM treatment on cognitive function, to that targeting a specific gene mutation and abolishing related epileptic activity may result in improved cognitive functions (10).…”