RNA-targeted
therapeutics offers inherent advantages over small molecule drugs wherever one out of several splice variant
enzymes should be inhibited. Here, we report the use of
Monarsen, a 20-mer
acetylcholinesterase-targeted antisense agent with three 3'-2'o-methyl-protected
nucleotides, for selectively attenuating the stress-induced accumulation of the normally rare, soluble "readthrough"
acetylcholinesterase variant AChE-R.
Acetylcholine hydrolysis by AChE-R may cause muscle fatigue and moreover, limit the
cholinergic anti-inflammatory blockade, yielding
inflammation-associated pathology. Specific AChE-R targeting by
Monarsen was achieved in cultured cells, experimental animals, and patient volunteers. In rats with
experimental autoimmune myasthenia gravis, oral delivery of
Monarsen improved muscle action potential in a lower dose regimen (nanomolar versus micromolar), rapid and prolonged manner (up to 72 h versus 2-4 h) as compared with the currently used small molecule
anticholinesterases. In central nervous system neurons of both rats and cynomolgus monkeys, systematic
Monarsen treatment further suppressed the levels of the proinflammatory
cytokines interleukin-1 (IL-1) and
IL-6. Toxicology testing and ongoing clinical trials support the notion that
Monarsen treatment would offer considerable advantages over conventional
cholinesterase inhibitors with respect to dosing, specificity, side effects profile, and duration of efficacy, while raising some open questions regarding its detailed mechanism of action.