Gene-based therapies: overview and application to chromosome 15q

Precision therapeutics. Ongoing research in precision therapies in neurological disorders, including 15q-related disorders, is occurring in three spaces: 1) gene therapy, 2) anti-sense oligonucleotides (ASOs), and 3) small molecules (repurposing existing drugs or generating new drugs), where the latter is primarily focused on addressing the symptoms of genetic disorders (i.e. seizures) rather than the cause (i.e gene dysfunction). Each of these forms of therapy has particular challenges, including, critically, the delivery method. The blood-brain barrier (doing its job well) restricts the access of large or hydrophilic medications to the central nervous system (CNS), therefore scientists building these drugs must not only consider efficacy and safety of the drug itself, but also efficacy and safety of the delivery method to the CNS. Below we explore ASOs and gene therapies and their application in 15q-related disorders in more depth. We will not discuss small molecule therapies here as the topic is too broad in scope for the purposes of this post, and we would like to focus primarily on genetically-based therapies.

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Expanding clinical actionability in GLUT1 Deficiency through a blood-based biomarker

GLUT1DS. Disease-causing variants in SLC2A1 are associated with a rare genetic neurometabolic condition known as GLUT1 Deficiency Syndrome (GLUT1DS). While GLUT1DS is typically diagnosed through molecular genetic testing, the diagnostic strategy in some cases includes lumbar puncture to measure cerebrospinal fluid (CSF) glucose to confirm the diagnosis. In a recent study, Mochel and collaborators performed a multicenter validation study of a blood-based biomarker for GLUT1DS. Here is a brief review on their publication and the utility of molecular biomarkers in GLUT1DS and genetic epilepsies more broadly.

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The future of biomarker development in rare disease

CNS Biomarkers. In the last two days, our team attended the Workshop for Multimodal Biomarkers in CNS Disorders held at the National Academies of Sciences, Engineering, and Medicine in Washington, DC. This conference provided a needed review of the current state of multimodal biomarker discovery and development. While most of the speakers focused on more common CNS disorders such as Alzheimer’s disease and neuropsychiatric disorders, there stands to be important lessons that can be translated into the rare disease field. Here is what we learned about the clinical utility of biomarkers and their potential as we move towards precision medicine in rare disease.

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The landscape of epilepsy genetics in 2023

Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.

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How precise is precision medicine – the difference between theoretical guidelines and real-world practice in pediatric epilepsy

Precision medicine. This post continues the discussion on how we can make sense of clinical data in the absence of outcomes in the context of precision medicine – a concept that drives much of what we do on a research basis. The fundamental idea is that clinical care in pediatric epilepsies can be personalized and tailored to underlying etiologies. With continual progress in gene curation and variant interpretation alongside clinical knowledge, we typically expect that treatment suggestions are immediately implemented after the discovery of the causative genetic etiology. For example, a child with early onset epileptic encephalopathy is found to have a gain-of-function variant in SCN8A and is almost immediately started on a sodium channel blocker such as Trileptal. However, to what extent is this the case? In the context of precision medicine, how precise are we exactly?

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Precision medicine in the absence of outcomes

EMR. Genomic data is increasingly available for large patient cohorts. In parallel, healthcare is increasingly digitized and large amounts of data can easily be extracted and analyzed at the click of a button. In principle, this should provide tremendous opportunities to understand how epilepsy care can be personalized based on genetic factors. However, we quickly run into challenges. Obtaining information on seizure frequencies, for example, requires manual chart review. Trying to understand how a person’s genetic makeup affects responses to anti-seizure medications is therefore not possible in large healthcare systems where related questions in other diseases can increasingly be answered. Here is a brief overview of how we can meaningfully engage with clinical data when outcomes are simply not available. Continue reading

DNM1 and when transcripts matter more than genes

What comes next. Earlier this month, Ingo made a bit of a splash at the American Epilepsy Society Annual Course, with his surprising comment that, in some contexts, “genes don’t matter.” This was in reference to transcripts and gene expression, which ultimately determine if and how variants can cause disease. In this post, I wanted to explore this idea, diving into the world of transcripts and their increasing relevance in approaching diagnosis and treatment of genetic epilepsies and neurodevelopmental disorders. And I wanted to share one of the most surprising findings in epilepsy genetics in 2022, namely, how examining transcripts rather than genes helped us understand how an intronic variant can be dominant-negative. Continue reading

Walking in Memphis – TARGETing Epilepsy at St. Jude

Memphis, TN. Prior to this year’s AES meeting, the epilepsy genetics community descended upon St. Jude Children’s Research Hospital in Memphis. I had previously largely associated St. Jude with pediatric cancer treatment, but within the last few years, a large-scale pediatric neuroscience program was launched, putting Memphis on the epilepsy genetics map. And with Heather Mefford’s new lab, the program at St. Jude includes one of the major epilepsy genetics groups. While blogging about scientific meetings is always tricky, one particular quote from the first day struck me as particularly relevant for the current state of therapeutic development: “quick, but not too quick”. Here is where the field of epilepsy genetics and precision medicine finds itself at the end of 2022. Continue reading

Precision medicine is instructive when it fails

KCNT1. This is my third blog post on our precision medicine review by Knowles and collaborators. In this post, I wanted to review the experience with precision medicine in the epilepsy community since the initial precision medicine road map that we published in 2015.  Here is a quick summary of why the community’s experience with quinidine was an important lesson for the future. No, it did not fail, it simply revealed a weakness in the way we introduce repurposed medications into clinical practice and how we think about them. Continue reading

Epilepsy genetics is more than just sending gene panels

Genetic testing. I smiled into my camera during our virtual Wednesday teaching session — pausing for effect. One of our junior team members has just made the statement that one of our patients qualified for a sponsored genetic testing program. I politely corrected them: “I think what you wanted to say was that this program qualifies for doing genetic testing on our patient”. The focus of epilepsy genetics is changing, shifting away from genetic testing to what genetic tests mean and how we can use them for better treatment. However, getting to a diagnosis requires the ability to perform genetic testing in the first place. And the framework for how this can be accomplished is vastly different within the US and internationally. In this second blog post on our review on epilepsy precision medicine, I would like to revisit the current state of genetic testing in the epilepsies. And yes, genetic testing should be standard of care and affordable for people with epilepsy. It’s that simple. Period. Continue reading