Antisense Oligonucleotide (ASO) Conjugate Development Services
Introduction
Antisense oligonucleotides (ASO) have advantages in gene silencing and disease treatment, but naked ASOs have low biological stability and are easily degraded by nuclease in vivo. To improve the stability and delivery efficiency of ASO, the conjugation of ASO with specific molecules has also been applied in addition to nucleotide modification. Creative Biolabs offers custom ASO conjugate services with various strategies and methods from perspectives of design, synthesis, and functional testing based on customer needs.
ASO conjugates
Peptide-Conjugated ASO
Peptide-conjugated ASO consists of one or more residues of a linear or cyclized peptide covalently linked to an oligonucleotide or its analog. Peptides offer the possibility of targeted drug delivery due to their good specificity; lower immunogenicity provides a good safety profile; the molecular weight of peptide-conjugated ASO is smaller, but the half-life can be prolonged with appropriate modifications.
Lipid-Conjugated ASO
The lipid moiety acts as a carrier and is linked to the oligonucleotide moiety by chemical bonds. Lipid-conjugated ASO exhibited better hydrophobicity, membrane permeability, and internalization efficiency, maintaining high dose tolerance in vivo.
GalNAc-Conjugated ASO
GalNAc, a lactose analog, is a ligand for asialoglyco protein receptor (ASGPR) with high affinity. ASGPR mainly expresses on the surface of hepatocytes and promotes the entry of ASO into cells through endocytosis. GalNAc-conjugated ASO drugs are usually synthesized by covalently coupling GalNAc to the 3'-end of ASO in a trivalent manner. This conjugation mode allows the drug to maintain high stability and biological activity.
Antibody-Conjugated ASO (AOC)
With strong binding ability and stable structure, AOC can achieve precise targeted delivery of ASO, which is suitable for the treatment of diseases requiring highly specific targeting. However, it may cause immune reactions during use, so immunogenicity needs to be thoroughly evaluated when designing and synthesizing AOC drugs.
Polymer-Conjugated ASO
Polymer-conjugated antisense oligonucleotides (ASO) can enhance the stability and solubility of drugs, control drug delivery, and improve drug efficacy and pharmacokinetics. Polymers can be conjugated with ASO through streptavidin/biotin interactions, covalent bonds, electrostatic interactions, and other mechanisms.
Small Molecule-Conjugated ASO
Small-molecular-conjugated ASO improves the pharmacokinetics of ASO drugs as well as the uptake of conjugates by target cells and enhances their endosomal release. These are achieved by utilizing specific receptor interactions or by conjugation of ASOs to lipophilic small molecules. The enhanced endosomal release represents that ASO can effectively escape into the cytosol through the endosomal mechanism to achieve self-delivery of the drug.
Fluorophore-Conjugated ASO
Fluorophore conjugated ASO refers to the complex of fluorescent dye (or fluorophore, fluorochrome, fluorescent probe) and ASO linked by specific chemical bonds (e.g., covalent bonds). Fluorophore-conjugated ASO facilitates visualization, quantification, tracking, and high sensitivity when used as probes.
Aptamer-Conjugated ASO
Aptamers are ssDNA, RNA, peptides, or short nucleic acid sequences of 70-100nt in length, which are usually obtained from nucleic acid molecular libraries by systematic evolution of ligands by exponential enrichment (SELEX). Its advantages are a short detection cycle, low detection limit, high affinity, and strong specificity, which can recognize and bind to specific target molecules (e.g., proteins, peptides, small molecule compounds, metal ions) with high specificity. Aptamer-conjugated ASO can improve the targeting specificity and delivery efficiency of ASO drugs, and reduce adverse reactions.
The table below summarizes some of the ASO conjugates in clinical trials:
| Conjugates | Name | Molecular target | Design | Disease |
|---|---|---|---|---|
| GalNAc | Olezarsen | ApoC3 | 5-10-5 MOE (PS) | Cardiovascular |
| Pelacarsen | LPA | 5-10-5 MOE (PO/PS) | Reduces lipoprotein(a) up to 80% | |
| Donidalorsen | KLKB1 | 5-10-5 MOE (PO/PS) | Hereditary angioedema | |
| Cimdelirsen | GHR | 5-10-5 MOE (PO/PS) | Acromegaly | |
| Antibody | ACHIEVE | DMPK | TfR1-conjugated | Myotonic dystrophy type 1 |
| αCD22 Ab-ASO conjugate | MXD3 | αCD22 Ab-Cycloalkyne azide-ASO | Leukemia | |
| Peptide | PGN-EDO51 | DMD Exon51 | EDO-ASO | DMD |
| ENTR-601-44 | DMD Exon44 | EEV | DMD |
Applications of ASO Conjugates
Treatment of diseases
The therapeutic effect of ASO drugs is improved by coupling them with other molecules. Antibody-coupled ASO is effective in the treatment of Duchenne muscular dystrophy. The efficiency of targeted gene silencing after drug coupling is improved, and the therapeutic effect on various cancers is also improved to a certain extent.
Treatment of genetic diseases
ASO conjugation technology is used to treat genetic diseases by gene editing, introducing exogenous normal genes to replace defective genes, or compensating the genome of target cells, so that the cells can restore normal function and achieve the purpose of treating genetic diseases.
Drug development and screening
ASO conjugation technology verifies drug targets or screens and optimizes drugs by targeting specific mRNA or protein to improve the efficacy of small molecules, antibodies, or other drugs and reduce biological toxicity and side effects.
Biomedical research
ASO conjugation technology is widely used in biomedical research. ASO can be conjugated with fluorescent molecules and can be observed in real time, providing a powerful tool for the evaluation of drug efficacy.
If you are interested in ASO conjugated technology services, please feel free to contact us, Creative Biolabs will be glad to provide you with professional solutions and quality service experience.
