ETX101 for Dravet Syndrome

Encoded is developing ETX101, a potential one-time, disease-modifying gene regulation therapy for SCN1A+ Dravet syndrome. ETX101, Encoded’s lead program, is specifically designed to address the underlying cause of Dravet syndrome, the most common developmental and epileptic encephalopathy. ETX101 is a cell-selective gene therapy in development to potentially address the full range of seizure, cognitive, behavioral, developmental and motor manifestations of Dravet syndrome.

Dravet Syndrome Overview

A mutation in the SCN1A gene causes about 85% of Dravet syndrome cases. Dravet syndrome is a disease of haploinsufficiency, meaning that only one of the two copies of the SCN1A gene works properly, leading to production of only half of the necessary sodium channels, NaV1.1, in neurons.

Devastating Disease in Pediatric Population

  • Seizures typically present in the first year of life

Severe Disease with Impact on Mortality
and Neurodevelopment

  • Up to 15-20% mortality rate before adulthood
  • Significant developmental delay and cognitive disability

Large Unmet Need

  • 1 : 15,500 incidence rate
  • 35,000 patients in the US, EU3 (France, Germany, Italy), Canada and Japan

No Disease-Modifying Therapies

  • Approved therapies reduce seizure burden but have limited impact on neurodevelopment

NaV1.1 is primarily expressed in inhibitory interneurons, the cell type responsible for reducing neuronal activity in the brain. With reduced NaV1.1, the brain may become hyperactive, causing seizures and other clinical manifestations that significantly impact the lives of affected children and their families. Currently approved Dravet syndrome treatments are chronically administered and purely symptomatic, aiming only to reduce seizure frequency or severity. Despite the currently available treatments, very few people with Dravet syndrome experience sustained periods of seizure freedom.

Sources: Wu YW, et al. Pediatrics 2015;136:e1310–15;; NORD; Symonds JD, et al. Hum Mutat. 2020 Feb;41(2):363-374; Gataullina S, Dulac O. Seizure 2017;44:58–64; Catarino CB, et al. Brain 2011;134:2982–3010; Wirrell EC, et al. Pediatr Neurol 2017;68:18–34.e3; Lagae L, et al. Dev Med Child Neurol 2018;60:63–72

How ETX101 Works

ETX101 delivers a transgene coding for an engineered SCN1A-specific transcription factor (eTFSCN1A) to upregulate, or increase, the expression of the endogenous SCN1A gene. Expression of the transgene is controlled by a GABAergic inhibitory neuron-selective regulatory element (REGABA). This approach increases the production of NaV1.1 at endogenous levels, thereby restoring inhibitory function and minimizing potential off-target effects.

ETX101 utilizes a clinically validated adeno-associated virus (AAV) capsid that has been extensively used in clinical trials for CNS disorders, as well as in a product with regulatory approval to treat spinal muscular atrophy, a rare neuromuscular disease. ETX101 is delivered via an intracerebroventricular (ICV) infusion, which is considered by neurosurgeons to be a safe and standard procedure to deliver antibiotics and enzyme-replacement therapies, among other drugs. Local ICV administration of AAV-mediated gene therapy to the CNS enhances delivery of the drug to key brain structures important for seizures and neurocognition, thereby increasing the potential for efficacy with a one-time administration.

Our preclinical data package for ETX101 demonstrates broad distribution in relevant CNS structures in non-human primates (NHPs), as well as long-term survival and reduction of seizures in the Dravet mouse model.

Underlying Cause of Dravet

Loss-of-function mutations occur in a single copy of the 6kb SCN1A gene (haploinsufficiency) encoding the voltage-gated sodium channel alpha-1 subunit NaV1.1
Lower density of NaV1.1 channels reduces the flow of sodium ions into the cell and therefore, reduces GABA release
Dysfunction in GABAergic inhibitory neurons causes uninhibited cortical excitation, leading to seizures and deficits in cognition, behavior and motor function

How ETX101 Works

AAV9 enters the cell by endocytosis in a receptor-mediated manner to deliver the therapeutic transgene, which predominantly exists as a non-replicating episome
Episome transcription initiates under the regulation of the REGABA promoter to produce eTFSCN1A preferably in GABAergic interneurons
eTFSCN1A binds to a conserved sequence upstream of the SCN1A transcription start site, promoting increased SCN1A expression
Increased SCN1A expression leads to increased density of membrane-associated NaV1.1 sodium channels, thereby restoring inhibitory function in GABAergic interneurons
Potential to address full range of disease manifestations by precisely upregulating SCN1A expression within GABAergic interneurons, while minimizing possible off-target effects

Developing ETX101

ETX101 has been generated using Encoded’s in-house capabilities – from preclinical discovery to our planned clinical trials. We anticipate leveraging this infrastructure for future development programs, paving an accelerated path from basic science through to the clinic.