2024 is proving to be a promising year for the advancement of targeted therapies for Dravet syndrome, including some newly enrolling clinical studies to investigate a novel genetic-based therapy from Encoded Therapeutics which we will discuss further in today’s blog post. Dravet syndrome is caused by mutations in one copy of the SCN1A gene, which codes for a sodium channel, called Nav1.1, that is used by cells in the brain for communication. Mutations in SCN1A that cause Dravet syndrome generally result in about a 50% reduction of healthy Nav1.1 sodium channels (which can also be referred to as a “haploinsufficiency”. Targeted genetic-based therapies aim to restore the levels of healthy Nav1.1 sodium channels. Stoke Therapeutics recently announced some encouraging results from Phase 1/2 and open-label extension studies for their RNA-based therapy STK-001 (covered in more detail in this recent blog post). Preclinical studies in animal models continue to support the efficacy of a variety of genetic-based approaches to modify the disease-course of Dravet syndrome, but the study data reported by Stoke shows for the first time in human patients that treating Dravet syndrome at the root cause could treat symptoms beyond seizures. In addition to these new data releases from Stoke, Encoded Therapeutics recently received approvals to begin clinical studies for their genetic-based therapy, ETX101, in the United States, Australia, and the United Kingdom. There are many differences in how ETX101 works versus STK-001, but the goal of increasing expression of healthy Nav1.1 sodium channels from SCN1A is the same.
While the most direct approach to a haploinsufficiency like Dravet syndrome would be to send in a replacement for the faulty gene, the SCN1A gene is too large to fit inside the current ‘delivery packaging’. To overcome this hurdle, a lot of research has focused on ways that the existing healthy copy of the gene could instead be upregulated to make more intact Nav1.1 sodium channels. ETX101 delivers a regulatory gene that acts to increase expression of SCN1A by binding to the regions of the DNA in front of the start of the gene to instruct the cell to make more. The specialized gene that ETX101 will be delivering to cells is called an engineered transcription factor (eTF). This eTF is much smaller than the SCN1A gene, so it can fit within a commonly used delivery packaging, called an adeno-associated viral (AAV) vector. The AAV vector is the empty shell of the original adeno-associated virus, with any of the internal genetic material of the virus removed, which allows it to hold the therapeutic material and deliver it to cells. ETX101 will also contain special instructions to target the therapy to a specific subset of cells in the brain that have been identified as the most impacted by SCN1A haploinsufficiency. These cells are called GABAergic inhibitory interneurons, and when they are working correctly, they help to “put the brakes” on electrical activity in the brain. The loss of sodium channels impacts the ability of these neurons to do this, leading to increased electrical activity that contributes to symptoms of Dravet syndrome such as seizures. In mouse models of Dravet syndrome, ETX101 has been effective at increasing expression of SCN1A, decreasing seizures, and increasing survival. Additional work in non-human primates provided evidence that ETX101 was well tolerated and could be delivered broadly across the brain. (Tanenhaus et al, 2022)
ETX101 is expected to be a one-time treatment of a single dose delivered directly to the CNS via an intracerebroventricular (ICV) infusion. The AAV vector, in this case AAV9, delivers DNA containing the code for the eTF to neurons, where it can remain long-term. This delivered DNA is not intended to integrate into, edit, or change the patient’s existing DNA. It will remain as a circular strand of DNA (called an episome) where it can express the eTF, which can then interact with the patient’s existing DNA to target upregulation of expression from the SCN1A gene. The goal is that this will increase healthy numbers of the sodium channel in the cells that need it, correcting the dysfunctional signaling of these neurons and restoring balance to the electrical activity in the brain. Hopefully this will address seizures as well as other symptoms of Dravet syndrome and truly modify the disease course.
As mentioned above, Encoded has now received approval to begin several initial studies for ETX101 in patients with Dravet syndrome. In the US the study is called ENDEAVOR. ENDEAVOR is a two-part Phase 1/2 dose-escalating study of ETX101 in infants and young children with SCN1A+ Dravet syndrome aged 6 months to less than 36 months. In Part 1 of the study, up to two different doses of ETX101 will be evaluated in 4 participants, with the primary aim to evaluate the safety and tolerability of ETX101, to evaluate preliminary efficacy, and to contribute to therapeutic dose selection. Part 2 is planned following demonstration of safety and efficacy in ENDEAVOR Part 1. You can find more about this study from visiting clinicaltrials.gov (NCT05419492) or the website for Encoded Therapeutics. Currently, the study site at Cook Children’s Medical Center in Fort Worth, Texas, is enrolling, and another site at the University of California San Francisco is in the progress of being activated. You can find links to additional information at the end of this blog.
It is truly a groundbreaking time in the development of gene therapies for human disease, and it is exciting to see Dravet syndrome at the forefront. It is important to recognize that these are still experimental studies to understand if these therapies are safe and effective. While there are a growing number of examples of successful genetic therapies across many human diseases, there is still a lot we are learning from the patients that are being treated. The data from Stoke Therapeutics stands as a proof-of-concept that addressing Dravet syndrome at the genetic source could possibly be disease modifying, but again, these trials still need to be completed until we know if this can be considered a true treatment for Dravet syndrome. Similarly, ETX101 holds much potential to address Dravet syndrome at the source and provide a treatment that modifies the course of the disease.
I understand the challenge of balancing excitement for future advancements with the urgent need for these treatments now. However, it’s crucial that these studies progress with the careful and thoughtful study designs that regulators carefully review, approve, and continue to monitor. Despite being a rare disease, the Dravet community has remained steadfast in its support of research. Families have tirelessly fundraised to fund research that has paved the way for important advancements in therapies. Even more importantly, many families and patients have been willing to participate in clinical studies.
All of those efforts are why therapeutic development for Dravet syndrome has continued to propel forward and why it remains a focus for therapeutic companies. Thank you to the many families that have participated in all these efforts that have led to the existing and novel therapies in development for Dravet syndrome.
Resources for more information:
- ENDEAVOR study listing: NCT05419492
- Actively enrolling site:
Cook Children’s Medical Center; Fort Worth, Texas
Contact: Dianna Grado, RN
email: Grado@cookchildrens.org
phone: (682)885-2844
- Actively enrolling site:
- Information on ETX101 from Encoded Therapeutics: https://encoded.com/programs/etx101-for-dravet-syndrome/
- More information on studies for ETX101, including the WAYFINDER study in Australia and EXPEDITION study in the UK: https://encoded.com/programs/clinical-studies/
