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pyridostigmine were withdrawn from it and treated with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.