Haploinsufficiency, Dominant Negative, and Gain-of-Function Mechanisms in Epilepsy: Matching Therapeutic Approach to the Pathophysiology

Gemma L. Carvill, Tyler Matheny, Jay Hesselberth, Scott Demarest*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

This review summarizes the pathogenic mechanisms that underpin the monogenic epilepsies and discusses the potential of novel precision therapeutics to treat these disorders. Pathogenic mechanisms of epilepsy include recessive (null alleles), haploinsufficiency, imprinting, gain-of-function, and dominant negative effects. Understanding which pathogenic mechanism(s) that underlie each genetic epilepsy is pivotal to design precision therapies that are most likely to be beneficial for the patient. Novel therapeutics discussed include gene therapy, gene editing, antisense oligonucleotides, and protein replacement. Discussions are illustrated and reinforced with examples from the literature.

Original languageEnglish (US)
Pages (from-to)1500-1514
Number of pages15
JournalNeurotherapeutics
Volume18
Issue number3
DOIs
StatePublished - Jul 2021

Keywords

  • Antisense oligonucleotides
  • Epilepsy
  • Gene therapy
  • Genetics
  • Precision therapies

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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