Abstracts

Summary: Gene therapy is viewed as a promising tool for the treatment of epilepsy, particularly given the increasing identification of human genetic mutations associated with the disease. An overriding notion in medical genetics is that having identified a gene defect that causes disease, rescue of genotype by replacement of the defective gene should rescue the phenotype, and thus, cure the disease. Optimism for epilepsy treatment has been raised by studies that have successfully demonstrated inhibition of seizures after viral delivery of genes with subsequent expression of seizure-inhibiting product. However, such success has been achieved using over-expression in animal models of epilepsies that are not linked to a deficit in the gene being over-expressed, and thus, could be viewed more as a non-pharmacological approach to anticonvulsant delivery. Despite demonstrations of the feasibility of cell- or region-specific gene delivery, rescue of identified epilepsy gene mutations has thus far been ineffective in rescuing the disease phenotype. In this workshop, we will review progress and attempt to identify critical remaining obstacles to achieving a true cure for hereditary epilepsies by gene-based therapeutics. Dr. Thomas McCown will discuss key features in achieving efficient cell targeting and gene expression. Dr. Francesco Noe’ will discuss genetic approaches to chronic release of inhibitory agents as an anti-epileptic strategy. Finally, Dr. Beverly Davidson will discuss the comparative success of genetic rescue as a therapeutic approach in other heritable neurological diseases. Dr. Phil Schwartzkroin will then join the panel for an open discussion on what the future holds for gene therapy in the treatment of genetic epilepsies. Are current obstacles conceptual or largely technical? Do we simply need better control of targeting and expression of a particular gene, or do we require more thorough understanding of its dynamic regulation of function and mechanistic contribution to seizure susceptibility when defective? Importantly, how do we determine if the brain is simply irretrievably altered by the presence of a genetic defect throughout embryogenesis and/or postnatal development?