Abstracts

Rationale: Lafora disease (LD) is autosomal recessive, progressive myoclonus epilepsy (OMIM #254780), insidious cognitive decline and escalating myoclonic, visual, convulsive, and other seizures, with onset typically in teenagers followed by decline and death usually within 10 years. LD is caused by mutations in either the EPM2A (laforin) or EPM2B (malin) genes. The disease is characterized by the presence of Lafora bodies (LB) which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. LD mouse models deficient in laforin or malin, exhibit similar pathologies to LD patients including LB formation, widespread degeneration of neurons, impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Double-transgenic mouse model in which malin was deleted in all tissues and Gys1 was specifically deleted in the brain, rescues mice from neurodegeneration and results in a significant decrease in brain glycogen and LB. Methods: To evaluate the therapeutic potential of brain Gys1 inhibition, we used antisense oligonucleotides (ASO) to knockdown Gys1 in the two LD mouse models and measured Gys1 level, brain glycogen and neurodegeneration. Results: Lafora disease mice (n=6/group) treated with the Gys1 ASO administered by bolus ICV injection showed a dramatic reduction in brain glycogen synthase mRNA and protein leading to a dramatic reduction in glycogen levels in the brain, no LB formation and a robust reduction in neurodegeneration. Conclusions: ASOs with similar chemistries directed to targets in the CNS are currently in clinical trials for other neurological diseases and are presently delivered to patients by lumbar puncture. Our results provide a positive proof of concept that supports development of ASO therapy to Lafora disease patients that should potentially provide much needed relief in one of the severest diseases of adolescence. Funding: This study was funded by the families of patients with LD through Chelsea's Hope (USA), Associazione Italiana Lafora, France-Lafora, Tatjana and Milana Gajic Foundation (Bosnia-Herzegovina), Genome Canada, The Ontario Brain Institute, and Ionis Pharmaceuticals. SA was supported by the Sigrid Juselius Foundation, Maire Taponen Foundation, P䩶ikki and Sakari Sohlberg Foundation, and the Foundation for Pediatric Research. BAM holds the University of Toronto Michael Bahen Chair of Epilepsy Research.