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      New treatments for myasthenia: a focus on antisense oligonucleotides

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          Autoimmune myasthenia gravis (MG) is a neuromuscular disorder caused by autoantibodies directed against the acetylcholine receptor (AChR). Current symptomatic therapy is based on acetylcholinesterase (AChE) drugs. The available long-term current therapy includes steroids and other immunomodulatory agents. MG is associated with the production of a soluble, rare isoform of AChE, also referred as the “read-through” transcript (AChE-R). Monarsen (EN101) is a synthetic antisense compound directed against the AChE gene. Monarsen was administered in 16 patients with MG and 14 patients achieved a clinically significant response. The drug is now in a Phase II study. Further investigations are required to confirm its long-term effects.

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          Most cited references 27

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          Myasthenia gravis.

           D Drachman (1994)
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            Acute stress facilitates long-lasting changes in cholinergic gene expression.

            Acute traumatic stress may lead to post-traumatic stress disorder (PTSD), which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.
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              Virtues and woes of AChE alternative splicing in stress-related neuropathologies.

              The ACh hydrolyzing enzyme acetylcholinesterase (AChE) is a combinatorial series of proteins with variant N and C termini generated from alternate promoter usage and 3' alternative splicing. Neuronal AChE variants show indistinguishable enzymatic activity yet differ in their expression, multimeric assembly and membrane-association patterns. Differentially induced under stress, they show distinct non-hydrolytic properties and interact with different protein partners. Recent findings suggest that transcriptional and post-transcriptional regulation of AChE pre-mRNA is a neuroprotection strategy but might involve long-term damage. Specifically, variant-specific causal involvement of AChE in the progression of both neurodegenerative diseases (e.g. Alzheimer's and Parkinson's diseases) and neuromuscular syndromes (e.g. myasthenia gravis) raises the possibility that future therapeutic drugs might target specific AChE variant(s) or the corresponding RNA transcripts.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                10 January 2013
                : 7
                : 13-17
                [1 ]IRCCS S Camillo, Via Alberoni, Venice, Italy
                [2 ]Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128, Padova, Italy
                Author notes
                Correspondence: Corrado Angelini, IRCCS S Camillo, Via Alberoni 70, 30126, Lido, Venice, Italy, Email corrado.angelini@ 123456unipd.it
                © 2013 Angelini et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.



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