Antisense and/or immunostimulatory oligonucleotide therapeutics.
Antisense technology, which is based on a simple and rational principle of Watson-Crick complementary base pairing of a short oligonucleotide with the targeted mRNA to downregulate the disease-causing gene product, has progressed tremendously in the last two decades. Antisense oligonucleotides targeted to a number of cancer-causing genes are being evaluated in human clinical trials. While the first-generation phosphorothioate antisense oligonucleotides are in clinical trials, a number of factors, including sequence motifs that could lead to unwanted mechanisms of action and side effects, have been identified. The severity of the side effects of first-generation antisense oligonucleotides is mostly dependent on the presence of certain sequence motifs, such as CpG dinucleotides. A number of second-generation chemical modifications have been proposed to overcome the limitations of the first-generation antisense oligonucleotides. The safety and efficacy of several second-generation mixed-backbone antisense oligonucleotides are being evaluated in clinical trials. The immune stimulation affects observed with CpG-containing antisense oligonucleotides are being exploited as a novel therapeutic modality, with several CpG oligonucleotides being evaluated in clinical trials. A number of medicinal chemistry studies performed to date suggest that the immunomodulatory activity of CpG oligonucleotides can be fine-tuned by site-specific incorporation of chemical modifications in order to design disease-specific oligonucleotide therapeutics.
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, USA. sagrawal@hybridon.com
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Kandimalla
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018899:CpG Islands / Q000276:immunology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D012333:RNA, Messenger; D013873:Thionucleotides / Q000737:chemistry*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides