Acetylcholinesterase Antisense Oligonucleotides (EN101) as a Novel Treatment Strategy for ALS: A Mouse Model Study

Acetylcholinesterase Antisense Oligonucleotides (EN101) as a Novel Treatment Strategy for ALS: A Mouse Model Study Marc Gotkine, Gladis Gilinski, Leah Rozenstein, Oded Abramsky, Zohar Argov, Hanna Rosenmann, Jerusalem, Israel The study investigated the effect of EN101 on a transgenic mouse model of ALS. Previous evidence indicated that acetylcholinesterase (AChE) is involved in ALS. However, AChE enzyme inhibitors result in up-regulation of production of “readthrough” AChE, which could have detrimental effects. Therefore, it is expected that inhibiting AChE synthesis would be more beneficial. This can be done with antisense oligonucleotide technology. The study administered EN101 daily to the mouse model, comparing treated mice (N=11) to a control receiving saline (N=12). Disease onset was determined by weekly motor testing using a Rotarod device. Mice were also assessed daily for weight clinical motor score and survival. Treatment was found to create a 13day delay in onset and an 11-day delay in death compared to control mice. Therefore antisense oligonucleotides directed against AChE mRNA delay ALS progression in this model. This supports the theory that AChE is involved in the pathogenesis of ALS and that the inhibition of AChE synthesis could be used as a treatment.