Antisense treatment for myasthenia gravis: experience with monarsen.

Acetylcholinesterase pre-mRNA is susceptible to alternative splicing. Myasthenia gravis has been shown to be associated with the expression of the readthrough transcript (AChE-R), which, unlike the normal "synaptic" transcript (AChE-S) is not tethered to the post-synaptic membrane, but is a soluble monomer in the synaptic cleft. In rats with experimental autoimmune myasthenia gravis (EAMG), inhibition of production of AChE-R using antisense is associated with a significant reduction in synaptic expression of AChE-R mRNA and protein, with improved muscle strength and stamina and increased survival. Synaptic AChE does not appear to be significantly affected by the induction of EAMG or treatment with antisense to AChE-R. Monarsen (EN101) is a synthetic 20-base antisense oligodeoxynucleotide directed against the human AChE gene. It is modified to achieve stability for oral administration. Sixteen patients with seropositive myasthenia gravis who were responsive to pyridostigmine were withdrawn from it and treated with Monarsen. Fourteen patients experienced a clinically significant response. In some, the improvement was dramatic. Although the dose of pyridostigmine was not optimized before the study, the majority of responders achieved better Quantitative Myasthenia Gravis scores than on pyridostigmine. The response of an individual muscle group to Monarsen was related to the degree of deterioration following the withdrawal of pyridostigmine. Cholinergic side effects were conspicuous by their absence. Monarsen is now being investigated in a phase II study.