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.
- Molecular Weight: 7776.3 (free acid)
Trecovirsen sodium is a 25-mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene.
- Molecular Weight: 7179.15
Mipomersen (ISIS 301012 free base) is an antisense oligonucleotide inhibitor of apolipoprotein B (apoB). Mipomersen has anti-HCV effect and reduces the infectivity of the HCV. Mipomersen can be used for the research of homozygous familial hypercholesterolemia (HoFH).
- Molecular Weight: 8678.96 (free acid)
Sefaxersen sodium is a specific antisense oligonucleotide (ASO) targeting complement factor B (CFB). Sefaxersen sodium effectively reduces circulating levels of CFB, and can be used for geographic atrophy (GA) research.
- Formula: C244H381N113O88P20
- Molecular Weight: 6924.82
Viltolarsen (NS-065/NCNP-01) is a phosphorodiamidate morpholino antisense oligonucleotide. Viltolarsen binds to exon 53 of the dystrophin mRNA precursor and restores the amino acid open-reading frame by skipping exon 53, resulting in the production of a shortened dystrophin protein that contains essential functional portions. Viltolarsen has the potential for Duchenne muscular dystrophy (DMD) research.
- Molecular Weight: 8606.50
Eplontersen is a triantennary N-acetyl galactosamine (GalNAc3-7a)-conjugated antisense oligonucleotide targeting transthyretin (TTR) mRNA to inhibit production of both variant and wild-type TTR protein. Misfolded TTR induces amyloid fibrils formation in the heart and peripheral nerves, leads to amyloid TTR (ATTR) amyloidosis diseases.
- Formula: C296H414N86Na20O15P20S13
- Molecular Weight: 8665.5 (free acid)
Vupanorsen (sodium) is an N-acetyl galactosamine-conjugated antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. Vupanorsen (sodium) lowers triglycerides and atherogenic lipoproteins.
- Molecular Weight: 8647.00
Golodirsen (SRP-4053) is an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO). Golodirsen restores the reading frame of the Duchenne muscular dystrophy (DMD) gene by modifying the splicing process of the pre-mRNA, skipping exon 53. Golodirsen can restore the expression of the anti-myostatin protein. Golodirsen can be used for the research of duchenne muscular dystrophy (DMD).
- Molecular Weight: 5768.70
Trabedersen (AP 12009) is an orally active synthetic antisense phosphorothioate oligodeoxynucleotide that selectively targets human TGFβ2 mRNA. Trabedersen blocks TGFβ2 protein production, enters the nucleus without a transfection vector, and exerts dose-dependent antitumor effects. By reversing TGFβ2-induced immunosuppression and enhancing immune cytotoxicity, Trabedersen exhibits significant antiproliferative, antimigratory, and antimetastatic activities, with favorable safety profiles. Trabedersen is widely used in research related to various solid tumors, including anaplastic astrocytoma, glioblastoma, colorectal tumor, and melanoma.
- Molecular Weight: 3082.42 (free acid)
RGLS4326 sodium is a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17). RGLS4326 sodium can be used for the research of autosomal dominant polycystic kidney disease (ADPKD). RGLS4326 sodium inhibits miR-17 function in HeLa cells with an EC50 value of 28.3 nM.
- Formula: C305H481N138Na25O112P25
- Molecular Weight: 8647 (free acid)
Golodirsen (SRP-4053) sodium is an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO). Golodirsen sodium restores the reading frame of the Duchenne muscular dystrophy (DMD) gene by modifying the splicing process of the pre-mRNA, skipping exon 53. Golodirsen sodium can restore the expression of the anti-myostatin protein. Golodirsen sodium can be used for the research of duchenne muscular dystrophy (DMD).
- Molecular Weight: 6368.00
(R/S)-Alicaforsen is the racemate of Alicaforsen composed of R and S configurations. Alicaforsen is a 20-base antisense oligonucleotide inhibiting ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking to the site of inflammation.
- Formula: C196H230N68Na19O105P19S19
- Molecular Weight: 6435.2 (free acid)
Aprinocarsen (ISIS 3521) sodium, a specific antisense oligonucleotide inhibitor of protein kinase C-alpha (PKC-α). Aprinocarsen sodium is a 20-mer oligonucleotide, it regulates cell differentiation and proliferation. Aprinocarsen sodium inhibits the growth of human tumor cell lines in nude mice. Aprinocarsen sodium shows the value as a chemotherapeutic compound of human cancers.
- Molecular Weight: 5616 (free acid)
- Formula: C211H275N76O119P19S19
- Molecular Weight: 6977.62
Drisapersen (Kyndrisa) is a 2'-O-methyl phosphorothioate RNA antisense oligonucleotide that induces exon 51 skipping. Drisapersen induces skipping of exon 51 during Dystrophin pre-mRNA splicing, allowing the synthesis of partially functional Dystrophin. Drisapersen can be used in research related to Duchenne muscular dystrophy.
- Molecular Weight: 8684.86
Olezarsen (ISIS 678354;IONIS-APOCIII-LRx) is a GalNAc-modified antisense oligonucleotide. Olezarsen binds to APOC3 mRNA and induces its degradation via ribonuclease H1-mediated sense strand cleavage, thereby reducing hepatic apolipoprotein C-III (apoC-III) synthesis. Olezarsen reduces plasma triglyceride, apolipoprotein B and non-high-density lipoprotein cholesterol levels. Olezarsen is applicable to research related to familial chylomicronemia syndrome, hypertriglyceridemia and atherosclerotic cardiovascular disease.
- Formula: C230H302N68O126P19S13Na19
- Molecular Weight: 7060 (free acid)
Ulefnersen sodium (ION363) is an Antisense Oligonucleotide (ASO) directed against the 6th intron of the fused-in sarcoma (FUS) transcript to silence FUS in a non-allele-specific manner. Ulefnersen sodium can reduce postnatal levels of FUS protein in the brain and spinal cord in disease-relevant mouse model of ALS-FUS , delaying motor neuron degeneration. Ulefnersen sodium can be used in the research of Amyotrophic Lateral Sclerosis (ALS) .
- Formula: C296H419N71Na20O163P20S13
- Molecular Weight: 8636 (free acid)
Pelacarsen sodium (ISIS 681257 sodium) is a GalNAc3-conjugated 2′-MOE-modified antisense oligonucleotide. Pelacarsen sodium reduces apo (a).
- Formula: C148H164N52Na13O77P13S13
- Molecular Weight: 4736 (free acid)
Cobomarsen sodium is an oligonucleotide inhibitor of miR-155. Cobomarsen sodium inhibits multiple gene pathways associated with cell survival (including JAK/STAT, MAPK/ERK and PI3K/AKT). Cobomarsen sodium can be used for the research of B-cell lymphoma.
- Molecular Weight: 7078.00
Tominersen (RG6042) is a second-generation 2′-O-(2-methoxyethyl) antisense oligonucleotide that targets huntingtin protein (HTT) mRNA and potently suppresses HTT production. Tominersen improves survival and reduces brain atrophy in mice. Tominersen can be used for the research of Huntington’s disease (HD).
- Molecular Weight: 6481.30
Tadnersen (BIIB078), an antisense oligonucleotide (ASO), selectively targets C9ORF72 transcript variants 1 and 3 that carry the expansion.
