Anti-sense approach to anticholinesterase therapeutics.
The acetylcholine-hydrolyzing enzyme, acetylcholinesterase, is the molecular target of approved drugs for Alzheimer's disease and myasthenia gravis. However, recent data implicate AChE splicing variants in the etiology of complex diseases such as AD and MG. Despite the large arsenal of anti-AChE drugs, therapeutic inhibitors are primarily targeted towards an active site shared by all variants. In contrast, anti-sense oligonucleotides attack unique mRNA sequences rather than tertiary protein structures. AS-ODNs thus offer a means to target gene expression in a highly discriminative manner using very low concentrations of drug. In light of the likely role(s) of specific AChE variants in various diseases affecting cholinergic neurotransmission, the potential contribution that anti-sense technology can make towards improved approaches to anti-AChE therapeutics deserves serious attention.
Soreq
H
H
Department of Biological Chemistry, Hebrew University, Jerusalem, Israel. soreq@cc.huji.ac.il
Seidman
S
S
D000110:Acetylcholinesterase / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy; D002799:Cholinergic Fibers / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009157:Myasthenia Gravis / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000110:Acetylcholinesterase