GalNAc-Oligonucleotide Conjugation

IntegrateRNA provides GalNAc conjugated oligonucleotides containing a monovalent/trivalent GalNAc cluster attached to the 3'-end or 5'-end of the oligonucleotide. These conjugates are compatible with DNA, 2'-OMe, 2'-MOE, 2'F oligonucleotides including the options of phosphodiester or phosphorothioate linkages. To support clients' oligonucleotides therapeutic research, IntegrateRNA offers GalNAc-siRNAs, GalNAc-ASOs, GalNAc-antagomiRs and GalNAc-conjugated nucleic acid therapeutics. GalNAc conjugation is a highly effective method for delivering therapeutic oligonucleotides to specific liver tissues/cells.

GalNAc (N-Acetylgalactosamine) is a naturally occurring sugar that binds to the asialoglycoprotein receptor (ASGPR), which is highly expressed in the membrane of hepatocytes (liver cells). Coupling GalNAc sugars to stabilized oligonucleotide molecules allows them to target liver cells and carry out their function, being shuttled into the cytoplasm as a result of the GalNAc-ASGPR binding. Also, by decorating it to a certein delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Furthermore, these GalNAc-oligonucleotides delivery systems have been used successfully in nonclinical species and in human to modulate the expression of many hepatocellular target RNAs.

• siRNA-GalNAc

Multivalent GalNAc-siRNA conjugates, where the multivalent GalNAc cluster is generally attached to the 3'-end of the sense strand of siRNA, can elicit robust gene silencing in hepatocytes both in vitro and in vivo without the aid of drug delivery agents. IntegrateRNA provides STC-siRNA-GalNAc and ESC-siRNA-GalNAc conjugates, in which specific chemical modifications are employed to improve the stability and affinity of siRNA.

• ASO-GalNAc

GalNAc conjugate was also employed in ASO drug development. With GalNAc conjugation, GalNAc-ASO showed ~10 fold greater potency than ASO without conjugate, which support lower does and less frequent dosing. GalNAc-ASO shows greater convenience foe patients, better potency and tolerability, and higher probability of compliance.

• AntagomiR-GalNAc

AntimiR is an antisense oligonucleotide that has been developed to silence microRNA (miRNA) for the treatment of intractable diseases. GalNAc conjugate technology has also been used for anti-miR (antagomir) delivery to enhance its in vivo efficacy and target efficiency. RG-101, a GalNAc-conjugated oligonucleotide targeting miR-122 developed by Regulus Therapeutics, is the first microRNA therapeutic for the treatment of hepatitis C virus (HCV).

• Nucleic acid therapeutics-GalNAc

GalNAc conjugate can also be used for liver-targeted delivery of other nucleic acid therapeutics and small molecules (such as miRNA and doxorubicin), resulting in certain biological effect in the cells.

Advantages

• Compatible chemical modification of oligonucleotide: 2'F, 2'OMe, 2'MOE, LNA, cEt, 5'VP, PS, PO
• Enhanced stability and affinity of oligonucleotide
• Years of experience in oligonucleotide design, synthesis, modification and conjugation

Application

• Animal experiment and preclinical research for RNA drug
• Oligonucleotide therapeutic development and optimization
• Oligonucleotide drug delivery to hepatocyte