Conjugates

RNA therapeutics, such as small interfering RNAs (siRNAs) and messenger RNAs (mRNAs), have shown great potential in treating various diseases by regulating gene expression. However, effective delivery of RNA molecules to specific tissues and cells has been a major challenge.

Conjugates are single chemical entities in which fully modified RNAs are conjugated to targeted ligands to help them find their way into specific cells or tissues in the body. It is like a "lock and key" system, where the lock is the receptor found on the target cell and the key is the ligand attached to the siRNA.

GalNAc Conjugates for RNA Delivery

GalNAc conjugates for RNA delivery are innovative pharmaceutical products designed to enhance the delivery of RNA therapeutics to target cells.

GalNAc conjugates consist of RNA molecules that have been chemically modified by conjugation to the sugar molecule GalNAc (N-acetylgalactosamine). GalNAc specifically binds to the asialoglycoprotein receptor (ASGPR) present on the surface of hepatocytes.

If multiple GalNAc units are combined into multivalent ligands, the binding affinity to the receptor increases exponentially, promoting optimal efficiency of RNA delivery to specific tissues and cells.

Figure 1. Conjugation of siRNA to an asialoglycoprotein receptor ligand derived from GalNAc facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo^[1].

Mechanism of Action of GalNAc Conjugates

1. Binding: The GalNAc portion of the conjugate specifically binds to ASGPR on liver hepatocytes.

2. Receptor-Mediated Endocytosis: Binding triggers receptor-mediated endocytosis, a process in which GalNAc-conjugated RNA is internalized into hepatocytes through the formation of vesicles.

3. Intracellular release: Once inside the hepatocyte, the RNA payload is released from the conjugate, allowing it to exert its therapeutic effect.

4. RNA interference or protein expression: Depending on the type of RNA therapeutic, the released RNA molecules can silence specific disease-causing genes via RNA interference (RNAi) or promote the production of therapeutic proteins via mRNA translation.

Advantages of GalNAc Conjugates

• Targeted Delivery: Specific binding of GalNAc to ASGPR enables precise targeting of hepatocytes, enhancing hepatic uptake and intracellular delivery of RNA therapeutics.
• Enhanced Potency: Efficient delivery of RNA molecules to target cells increases their therapeutic potency because higher concentrations of therapeutic RNA can reach the intended site of action.
• Reduced Off-target Effects: By selectively targeting hepatocytes, GalNAc conjugates minimize off-target effects on non-liver tissues, potentially improving the safety of RNA therapeutics.
• Versatility: GalNAc conjugates can be designed to deliver various types of RNA therapeutics, including siRNA for gene silencing and mRNA for protein replacement or expression.

Application Areas

GalNAc conjugates hold significant promise in the treatment of liver-related diseases, including:

• Hepatitis: RNA therapeutics delivered via GalNAc conjugates can effectively treat hepatitis infections by targeting viral replication pathways or modulating immune responses.
• Liver Cancer: GalNAc-conjugated RNA therapeutics can be used to inhibit the expression of oncogenic genes or deliver tumor suppressor proteins directly to liver cancer cells.
• Inherited Liver Diseases: By targeting hepatocytes, GalNAc conjugates can deliver RNA therapeutics that correct or compensate for genetic mutations associated with liver diseases, such as hemophilia or alpha-1 antitrypsin deficiency.

Reference

1. Nair, JK; et al. Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing. J. Am. Chem. Soc. 2014, 136(49): 16958-16961.

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