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The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis
Author(s) -
Brenner Talma,
HamraAmitay Yasmine,
Evron Tama,
Boneva Neli,
Seidman Shlomo,
Soreq Hermona
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0609com
Subject(s) - myasthenia gravis , acetylcholinesterase , cholinergic , acetylcholine , acetylcholine receptor , pathophysiology , aché , neuromuscular junction , medicine , endocrinology , pharmacology , immunology , receptor , chemistry , biology , enzyme , neuroscience , biochemistry
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 anticho‐linesterases 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.—Brenner, T., Hamra‐Amitay, Y., Evron, T., Boneva, N., Seidman, S., Soreq, H. The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J . 17, 214–222 (2003)