Antisense oligonucleotides for target validation in the CNS.
Although antisense oligonucleotides have been used in cell-based antisense experiments for nearly two decades, studies to investigate the function of CNS proteins in living animals were not successfully conducted until recently. Oligonucleotides are not transported across the blood-brain barrier to any appreciable extent. Consequently, these molecules need to be administered directly into the brain. Antisense approaches may be especially suited to investigation of CNS proteins. Due to their specificity, antisense sequences can more easily and selectively distinguish between closely related proteins, such as receptor subtypes, in contrast to the more traditional pharmacological agents such as small molecule ligands. This review discusses some unique technical aspects surrounding oligonucleotide delivery to the brain, and summarizes some of the more noteworthy applications of antisense tools to the study of CNS protein function during the past two years.
Ho
S P
SP
DuPont Pharmaceuticals, Wilmington, DE 19880, USA. siew.p.ho@dupontpharma.com
Hartig
P R
PR
D000698:Analgesia / Q000379:methods; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D015195:Drug Design; D004341:Drug Evaluation / Q000379:methods*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D008322:Mammals; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000502:physiology; D009765:Obesity / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D011954:Receptors, Dopamine / Q000145:classification / Q000187:drug effects; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000502:physiology; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology; D015203:Reproducibility of Results
D002491:Central Nervous System Agents; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; D011956:Receptors, Cell Surface; D011954:Receptors, Dopamine; D018013:Receptors, Neuropeptide; D011957:Receptors, Opioid