title: Antisense apolipoprotein B therapy: where do we stand?
abstract: OBJECTIVE
  Antisense oligonucleotides are novel therapeutic agents that reduce the number of specific mRNAs available for translation of the encoded protein. ISIS 301012 is an antisense oligonucleotide developed to reduce the hepatic synthesis of apolipoprotein B-100. Apolipoprotein B-100 is made in the liver, and antisense oligonucleotides preferentially distribute to that organ, so antisense apolipoprotein B-100 may have potential as an efficacious lipid-lowering agent.
  
  
  RESULTS
  Recently, in healthy volunteers and in mild dyslipidaemic patients, this strategy as monotherapy or in conjunction with statins has shown unparalleled efficacy in reducing apolipoprotein B-100 and LDL-cholesterol. Tolerance for this novel therapy is encouraging and safety concerns currently only relate to mild injection-site reactions and rare liver-function test abnormalities. It should be noted, however, that these safety results were obtained in relatively few individuals.
  
  
  CONCLUSIONS
  ISIS 301012 has initially shown promising results in experimental animal models, and in clinical trials in humans. Besides the effect of reducing apolipoprotein B-100 and LDL-cholesterol, this compound also significantly lowers plasma triglycerides. Safety concerns related to the drug include increased liver-function tests. To date no evidence of hepatic steatosis has been reported. Nonetheless, clinical trials of longer duration are required to demonstrate further safety.
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: Fatima
authors.initials: F
authors.lastname: Akdim
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D015195:Drug Design; D050171:Dyslipidemias / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D006937:Hypercholesterolemia / Q000628:therapy; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050155:Lipogenesis / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger