Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure
Annual rept. 15 Jul 2001-14 Jul 2002
HEBREW UNIV JERUSALEM (ISRAEL)
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Alternative splicing induces, under cholinergic imbalance, 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, both 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. While animals treated with placebo or conventional anticholinesterases continued to deteriorate, a 4-week 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 imbalances.
- Stress Physiology