Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2002
- Accession Number
- ADA416332
Entities
People
- Hermona Soreq
Organizations
- Hebrew University of Jerusalem