en101 and Myasthenia-Gravis

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.

Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Humans; Myasthenia Gravis; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Protein Isoforms; Receptors, Cholinergic

Myasthenia gravis (MG) is an autoimmune disorder usually caused by antibodies against either the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) at the neuromuscular junction. Neuromuscular transmission failure results in muscle fatigue and weakness that can be treated symptomatically with acetylcholinesterase inhibitors (AChEIs). Long-term treatment with nonselective AChEIs may have considerable drawbacks; thus, this medication is ideally tapered when strength improves. Patients with AChR antibodies respond beneficially to treatment, whereas patients with MuSK antibodies generally do not. Recently, the selective AChEI EN101, which specifically targets the isoform of "read-through" AChE (AChE-R), has been developed and may be of importance for symptomatic relief in AChR-antibody seropositive MG. This article is a review of the mechanisms, therapeutic effects, and drawbacks, with both old and new AChEIs in MG.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Humans; Immunologic Factors; Immunosuppression Therapy; Myasthenia Gravis; Neuromuscular Junction; Oligodeoxyribonucleotides; Receptors, Cholinergic

We present further developments in the study of the antisense oligonucleotide EN101. Ongoing in vitro and in vivo studies demonstrate that EN101 is a TLR9-specific ligand that can suppress pro-inflammatory functions and shift nuclear factor kappa B (NF-κB) from the pro-inflammatory canonical pathway to the anti-inflammatory alternative pathway, which results in decreases acetylcholinesterase (AChE) activity. Preliminary results of a double-blinded phase II cross-over study compared 10, 20, and 40 mg EN101 administered to patients with myasthenia gravis. Patients were randomly assigned to one of three treatment groups in weeks 1, 3, and 5 and received their pretreatment dose of pyridostigmine in weeks 2 and 4. Thus far, all doses show a decrease in QMG scores, with a greater response to higher doses.

Topics: Acetylcholinesterase; Animals; Cross-Over Studies; Double-Blind Method; Humans; Myasthenia Gravis; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Rats

Topics: Animals; Cholinesterase Inhibitors; Cyclophosphamide; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Myasthenia Gravis; Oligodeoxyribonucleotides; Oligonucleotides, Antisense

Alternative splicing induces, under abnormal cholinergic neurotransmission, overproduction of the rare "readthrough" acetylcholinesterase variant AChE-R. We explored the pathophysiological relevance of this phenomenon in patients with myasthenia gravis (MG) and rats with experimental autoimmune MG (EAMG), neuromuscular junction diseases with depleted acetylcholine receptors. In MG and EAMG, we detected serum AChE-R accumulation. In EAMG, we alleviated electromyographic abnormalities by nanomolar doses of EN101, an antisense oligonucleotide that selectively lowers AChE-R in blood and muscle yet leaves unaffected the synaptic variant AChE-S. Whereas animals treated with placebo or conventional anticholinesterases continued to deteriorate, a 4 wk daily oral administration of EN101 improved survival, neuromuscular strength and clinical status in moribund EAMG rats. The efficacy of targeting only one AChE splicing variant highlights potential advantages of mRNA-targeted therapeutics for chronic cholinergic malfunctioning.

Topics: Acetylcholinesterase; Animals; Electromyography; Gene Expression; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Muscle, Skeletal; Myasthenia Gravis; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Rats; Rats, Inbred Lew; Receptors, Cholinergic; RNA, Messenger

Topics: Acetylcholinesterase; Administration, Oral; Clinical Trials as Topic; Humans; Isoenzymes; Myasthenia Gravis; Oligodeoxyribonucleotides; Oligonucleotides, Antisense