Restoring balance at the neuromuscular junction

Abstract

Argov and colleagues present the results of a Phase 1b trial of an oral antisense oligonucleotide, EN101 (Monarsen, Ester Neurosciences Ltd.), for treatment of myasthenia gravis (MG) in this issue of Neurology ®.1 The brief report and the authors' humble description of their study belie the remarkable story and potential for broad impact of their work. Why do I make this statement? 1) The science behind EN101 is fascinating and was rapidly translated to the clinic. 2) Of great surprise is that the agent is efficacious when given orally. 3) Human trials of antisense oligonucleotide technology have been disappointing, but this trial suggests a therapeutic benefit, which should bolster hope for this approach for drug development. 4) The work has broad implications beyond MG. It has long been appreciated that the AChE-synaptic (AChE-S) isoform is critical in terminating the action of ACh to prevent repeated activation of the acetylcholine receptor (AChR) (see figure). Supporting the importance of this critical function is the observation that mutations of the AChE-S gene lead to cholinesterase deficiency and a congenital myasthenic syndrome. The AChE-S is distributed through the primary and secondary synaptic clefts of …