Abstract
Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.
Highlights
As of October 2021, the Online Mendelian Inheritance in Man database lists 1,285 genes or loci involved in epilepsy
In addition to identifying LGI1-related epilepsy as a conformational disease, this study suggests a bright future for chemical chaperones as a precision therapy for certain monogenic epilepsies
A single ICV injection of a Kcnt1 gapmer anti-sense oligonucleotides (ASO) in a mouse model of KCNT1-epilepsy led to significant reduction in seizure frequency and increased overall survival compared to mice treated with a control sequence [86]
Summary
As of October 2021, the Online Mendelian Inheritance in Man database lists 1,285 genes or loci involved in epilepsy. By precision therapy or precision medicine, we mean any therapy that is either designed on the basis of the patient’s underlying genetic diagnosis or which has been found through clinical trials to have a significant effect in a particular genetic epilepsy (even if the mechanism of the therapy is unknown) This broad definition of precision therapy is in contrast with an ad hoc treatment of seizures without any attention being paid to the genetic diagnosis. We summarize the current state of precision therapies for monogenic epilepsy syndromes These therapies are quite diverse, and include molecular chaperones, use or avoidance of ion channel blockade for channelopathies, repurposing of medications, diets, gene therapies including anti-sense oligonucleotides (ASO), RNA interference (RNAi), and inhibitors of overactive cellular signaling [1]. We conclude with a discussion on the future of precision medicine in genetic epilepsies
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