Nucleic acid therapeutic drugs achieve durable, even curative, effects by inhibiting, adding, replacing, or editing genes. To enhance stability and evade immune recognition, CD BioGlyco offers drug delivery platforms that facilitate chemical modifications of nucleic acid molecules, with the GalNAc conjugation technology playing a crucial role in this process. This technology effectively increases small interfering RNA (siRNA) accumulation in target organs and facilitates cellular uptake. For silencing disease-causing genes in hepatocytes, siRNA therapeutics are conjugated to a triantennary GalNAc moiety, which targets the asialoglycoprotein receptor (ASGPR). ASGPR, abundantly expressed on hepatocytes, offers a defined pathway for liver-specific siRNA delivery. It selectively binds carbohydrates terminated with galactose or GalNAc residues, leading to clathrin-dependent receptor-mediated endocytosis upon ligand binding. ASGPR’s high expression on the hepatocyte sinusoidal membrane makes it an ideal receptor for hepatic siRNA delivery.
Fig.1 Delivery of siRNA and antisense oligonucleotide (ASO) using the GalNAc delivery system. (Wang, et al., 2024)
To maximize the delivery efficiency of oligonucleotides, we conduct structural improvements to the GalNAc design, specifically to optimize ligand interaction with the ASGPR. Our team achieves mass production of the core compounds in the GalNAc-L96 delivery system, advancing timely, affordable drug solutions. We synthesize GaINAC-L96, a triantennary GalNAc, and its related products, an innovative solution for liver hepatocyte therapy with precise targeting and delivery capabilities. Clients can attach our GaINAC-L96 products to a solid support through a specific linker before oligonucleotide synthesis, thus linking it to oligonucleotides.
Fig.2 Synthesis procedure of GalNAc-L96. (CD BioGlyco)
Targeting the market shortage and urgent need for core raw materials such GalNAc, our company leverages the technical expertise of our core research team accumulated over the years. Through straightforward preparation methods and processes, we efficiently produce GalNAc-L96 intermediates, ensuring both high yield and productivity.
Our synthesis process allows for the production of GaINAC-L96 and its analogs through meticulous control of raw materials and parameters. This method is straightforward, delivering a high yield and purity of the target product, resulting in specific purity levels.
Journal: Nature Communications
Technology: RNAseq, Bioinformatic analysis, Histopathology
IF: 14.7
Published: 2018
Results: In this study, the authors explored the mechanisms behind hepatotoxicity observed in rats exposed to pharmacologically exaggerated doses of trivalent GalNAc-conjugated siRNAs. They researched the potential causes such as intracellular accumulation of oligonucleotides, RNAi-mediated hybridization-based off-target effects, and perturbations in endogenous RNAi pathways. The authors found that most of the observed hepatotoxicity could be attributed to RNAi-mediated off-target effects rather than chemical modifications or disturbances in RNAi pathways. To address this, they introduced a thermally destabilizing chemical modification to modulate seed-pairing, which significantly enhanced the safety profile of GalNAc-siRNA in rats and potentially minimized hepatotoxicity across different species. This approach offers a promising strategy to improve the therapeutic index of RNAi-based therapeutics.
At CD BioGlyco, our GalNAc-L96 products represent a leading advancement in RNA-based drug delivery, leveraging structural improvements to optimize the interaction of triantennary GalNAc ligands with the ASGPR on hepatocytes. If you want to enhance the specificity and efficiency of siRNA therapeutics, contact us to learn more about our products!
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