The first patient was just enrolled in ENVISION, a natural history study being conducted by Encoded Therapeutics. There are 7 recruiting study sites, including one in Australia, and two additional sites are currently being added. The study does not provide any interventions, but rather is an observational study that follows children with Dravet syndrome over a period of 2 years to better understand seizures, neurodevelopment, motor development, and behavior, as well as the impact on caregivers.
Why are natural history studies important? Natural history studies are incredibly important to understanding and developing treatments for disease. In order to improve disease outcomes, the full spectrum and progression of the symptoms and comorbid conditions need to be completely characterized. Natural history studies help doctors and researchers recognize when aspects of disease first present, how they progress, the severity of the presentation, and how often the symptom occurs within the population. Some of these types of data could be found by retrospectively reviewing patient’s records and compiling that information together. However, there can be inconsistencies in that method that leave holes in our understanding. A natural history study, instead, collects the information prospectively, so the researchers can ensure consistency in the frequency of visits to the doctor, consistency in the types of assessments that are used, and consistency in the domains that are measured. The information collected from a natural history study can then be used as a reference to inform health care decisions, including preventative interventions. The information from the study can also bring attention to comorbidities that are not targeted by current interventions, hopefully leading to increased research and new treatment approaches. Additionally, a longitudinal natural history study provides an average picture of disease progression. As disease modifying therapies become a clinical reality, natural history studies may be able to act as a comparison to an experimental treatment approach in a clinical trial to determine the effectiveness of the intervention on the progression of all the features of the disease.
Who is eligible to participate in ENVISION? Children aged 6 months to 60 months with a confirmed SCN1A-mutation and a clinical diagnosis of Dravet syndrome. Participants must have had seizure onset between the age of 3 and 15 months and normal development prior to the first seizure. The first figure below gives a high-level overview of the study (image provided by Encoded Therapeutics).
What will ENVISION measure? ENVISION will measure seizure frequency and seizure-free days using a seizure diary, as well as by keeping record of anti-epileptic or other interventional therapies utilized by patients. The study will assess more than just seizures, including cognitive, motor, language, social, emotional, and behavioral functioning as well as quality of life measures that all use standardized assessment tools. The figure below describes the key outcomes that will be measured in the ENVISION study (figure kindly provided by Encoded Therapeutics).
More information on the ENVISION study, including study sites and contact information, can be found at clinicaltrials.gov (NCT04537832).
Is Encoded Therapeutics developing a therapeutic approach to treat Dravet syndrome? Dravet syndrome is most commonly caused by a mutation in 1 copy of the SCN1A gene that reduces the expression of the sodium channel that is made by the SCN1A gene by about half (the remaining half is made by the second copy of the SCN1A gene that does not carrying a mutation). The sodium channel encoded by SCN1A, called Nav1.1, is important for regulating the electrical activity in the brain, and when Nav1.1 is disrupted neurons cannot communicate as effectively with each other resulting in seizure activity and likely contributing to the other comorbidities patients face. Ideally, gene therapy for Dravet syndrome would deliver a new copy of the SCN1A gene to restore the gene expression to normal levels. However, traditional gene therapy for Dravet syndrome has been hampered by the size of the SCN1A gene, which is too large for the current packaging used to deliver genetic therapies to cells. Encoded Therapeutics has developed an alternative approach to increase expression of the SCN1A gene called ETX101. Instead of delivering a new copy of the SCN1A gene, they aim to increase expression of SCN1A by modulating the regulation of the gene. ETX101 delivers a regulatory gene that acts to increase expression of SCN1A and, in turn, the sodium channel Nav1.1. When a gene within your DNA (like SCN1A) is expressed, the first step is to make a strand of messenger RNA (mRNA) that can then be used as instructions to make the final product: a protein (the sodium channel, Nav1.1). In order for a specific cell to know when and how much of a gene to express, there are regulatory regions in the DNA that act as markers to turn a gene on or off. Molecules that bind to these regulatory regions and turn gene expression on, off, up, or down, are called “transcription factors,” because the process of making mRNA from DNA is called “transcription.” The gene that ETX101 will be delivering to cells is an engineered transcription factor that will help to increase the expression of SCN1A. Because this engineered transcription factor is a much smaller size than the SCN1A gene, they are able to use an adeno-associated viral (AAV) vector to package the gene inside for delivery to cells. ETX101 is anticipated to be a one-time-treatment delivered directly to the brain, where the engineered transcription factor will be expressed in the major type of neurons that utilize the SCN1A gene in the hope that this will restore the function of these cells. Preclinical work has shown this approach to be effective in models of Dravet syndrome. Since this therapy specifically targets the root cause of Dravet syndrome, it is thought this could be a truly disease-modifying approach that has the potential to improve symptoms across multiple domains. Encoded Therapeutics hopes to begin a clinical trial for ETX101, called ENDEAVOR, later in 2021.
You can read more about Encoded Therapeutics at their website.
Encoded Therapeutics gave a talk about their experimental therapy, ETX101, and the ENVISION natural history study for DSF in summer 2020 that can be found here.