Antisense Oligonucleotides
Antisense Oligonucleotides (ASOs) usually refer to short, synthetic, single-stranded DNA or RNA (13-30 nucleotides). Following binding to the targeted mRNA or pre-mRNA, ASOs modulates RNA function by several different mechanisms.
1. ASOs can form an RNA–DNA hybrid that becomes a substrate for RNase H, resulting in target mRNA degradation.
2. ASOs can modulate gene expression via steric block of the ribosomal machinery, which can lead to reduced expression, modulation of splicing and/or restoration of a functional protein.
3. Binding of ASOs to pre-mRNA can alter splicing factor recruitment and regulate splicing events.
The first in vivo applications of ASOs showed limited clinical potential because of the high susceptibility of ASOs with an unmodified phosphoribose backbone to rapid degradation by endonucleases and exonucleases. The modifications in backbone, and sugar molecules give ASOs more affinity and stability. Phosphorodiamidate morpholino oligomers (PMO) are very resistant to nuclease and protease degradation and are mostly used in splicing modulation or translation inhibition. Chemical modifications at 2' position of ribose sugar ring such as 2’-O-methyl (2’-O-me), 2’-Fluoro (2’-F), 2’-O-methoxyethyl (2’-MOE) allow oligonucleotide to adopt RNA like C3’-endo sugar pucker, making it thermally stable.
ISIS 14803 is a 20-unit antisense phosphorothioate oligodeoxynucleotide that binds to hepatitis C virus (HCV) RNA at the translation initiation region of the internal ribosome entry site (IRES) and inhibits protein expression in cell culture.
- Molecular Weight: 8688.52
Cimdelirsen is a novel, ligand-conjugated, hepatic-targeted investigative antisense oligonucleotide designed to reduce growth hormone receptor (GHr) synthesis, thereby inhibiting deleterious effects of growth hormone (GH) hypersecretion and reducing circulating insulin-like growth factor-1 (IGF-1) levels in acromegaly patients.
- Molecular Weight: 7230.14
ATL 1102 (Avicursen) is a novel second-generation antisense oligonucleotide to CD49d mRNA
Aganirsen is a 25 mer DNA antisense oligonucleotide, which silences expression of insulin receptor substrate-1 (IRS-1).
- Formula: C296H415N83Na20O152P20S15
- Molecular Weight: 9128.16
Cimdelirsen is a novel, ligand-conjugated, hepatic-targeted investigative antisense oligonucleotide designed to reduce growth hormone receptor (GHr) synthesis, thereby inhibiting deleterious effects of growth hormone (GH) hypersecretion and reducing circulating insulin-like growth factor-1 (IGF-1) levels in acromegaly patients.
- Formula: C227H291O141P23
- Molecular Weight: 7220.63
PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to the regulatory region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death.
ISIS-2503 is a 20-mer antisense oligonucleotide that inhibits Ha-Ras expression
- Formula: C296H435N83O151P20S15
- Molecular Weight: 8672.64
Donidalorsen (ISIS-721744; IONIS-PKK-LRX free acid) is an antisense oligonucleotide targeting prekallikrein (PKK). Donidalorsen inhibits kallikrein activity and reduces the production of Bradykinin (HY-P0206) by specifically binding to and degrading PKK mRNA in the liver. Donidalorsen can be used in the research of hereditary angioedema.
- Formula: C172H218N57O88P15S15
- Molecular Weight: 5437.55
Cofirasersen is designed to reduce the expression of ENaC in the lung. ENaC is a sodium transport channel and believed to be hyperactive in cystic fibrosis, which is caused by mutations in the cystic fibrosis transmembrane regulator gene.
ISIS 5132 is a 20-base phosphorothioate oligonucleotide that specifically down-regulates c-raf expression.
ISIS 329993 (ISIS-CRPRx) is an antisense oligonucleotide targeting to C-reactive protein (CRP). ISIS-CRPRx has been tested in a rodent model of rheumatoid arthritis (RA) and was shown to improve the clinical signs of arthritis
- Molecular Weight: 5962.00
Sepofarsen (QR-110) is an RNA antisense oligonucleotide targeting to the p.Cys998X mutation (also known as the c.2991+1655A>G mutation) in the CEP290 gene.
- Formula: C223H262N74Na22O115P22S22
- Molecular Weight: 7228 (free acid)
Tilsotolimod (IMO-2125) sodium is a TLR9 agonist. Tilsotolimod sodium activates the TLR9 signaling pathway, triggers downstream pro-inflammatory and immunostimulatory pathways, enhances the uptake and killing of cancer cells, and induces adaptive immune responses. Tilsotolimod sodium is applicable to research related to melanoma and colorectal cancer.
PS220 sodium is an antisense RNA oligonucleotides. PS220 sodium can be used for research ofstudying muscular dystrophy.
SPC4061 an antisense nucleotide, is a potent PCSK9 inhibitor. SPC4061 targets the lock-in nucleic acid (LNA) of PCSK9 for the study of hypercholesterolemia and related diseases.
Monarsen (EN101) is a synthetic 20-base antisense oligodeoxynucleotide directed against the human AChE gene. Monarsen is used in the study of Autoimmune myasthenia gravis (MG), a neuromuscular disorder caused by autoantibodies directed against the acetylcholine receptor (AChR).
- Formula: C1632H2100N610O97P156S4
- Molecular Weight: 50742.05
Abetimus (LJP 394 free base) is an immunosuppressant consisting of four double-stranded DNA (dsDNA) oligonucleotides. Abetimus is capable of crosslinking anti-dsDNA antibodies on the surface of B cells, and decreases anti-dsDNA antibodies levels. Abetimus has the potential for research of systemic lupus erythematosus.
- Molecular Weight: 9056.30
Sefaxersen (IONIS-FB-LRx) is a specific antisense oligonucleotide (ASO) targeting complement factor B (CFB). Sefaxersen effectively reduces circulating levels of CFB. Sefaxersen can be used for geographic atrophy (GA) research.
- Molecular Weight: 7060.80
Zilganersen (ION373) is a gapmer antisense oligonucleotide targeting glial fibrillary acidic protein (GFAP). Zilganersen reduces excess glial fibrillary acidic protein produced by disease-causing variants in the GFAP gene and inhibits synthesis of GFAP. Zilganersen can be used for the research of Alexander disease.
- Formula: C₂₉₆H₄₃₇N₇₇O₁₅₆P₂₀S₁₃
- Molecular Weight: 8606.50
Obeversen is an antisense oligonucleotide that inhibits the synthesis of diacylglycerol acyltransferase 2 (DGAT-2). Obeversen can be used in the research of nonalcoholic fatty liver disease.
