The development of oligonucleotide therapeutics represents a paradigm shift in modern medicine, offering highly specific modulation of gene expression to address previously intractable diseases. CD BioGlyco specializes in overcoming the primary hurdle for these agents—efficient and targeted intracellular delivery—through our proprietary biantennary GalNAc-RNA delivery service. This advanced platform harnesses the highly selective mechanism of the asialoglycoprotein receptor (ASGPR) to ensure robust and exclusive delivery of your therapeutic RNA payload directly to liver hepatocytes.
Our biantennary GalNAc conjugate system is a precisely engineered, single chemical entity that combines the proven efficacy of multivalent targeting with optimized synthetic efficiency. By covalently linking two GalNAc sugar moieties to chemically stabilized RNA cargo, we achieve the critical multivalent interaction necessary for high-affinity binding to the ASGPR, driving receptor-mediated endocytosis into the target cells. This simple yet potent design is ideal for projects requiring liver-specific gene silencing via RNA interference (RNAi) or antisense oligonucleotide (ASO) mechanisms.
The core of our platform is the biantennary (divalent) GalNAc cluster, designed to achieve superior binding avidity to the ASGPR. While triantennary clusters are commonly used in the industry, our divalent approach is scientifically validated to enhance oligonucleotide potency significantly—by 5–10 fold in vivo over unconjugated agents—while offering a distinct advantage in synthetic cost and complexity, making your drug development process more scalable and cost-effective. This careful selection ensures high-capacity internalization and rapid uptake by hepatocytes.
To ensure the therapeutic RNA (siRNA or ASO) survives systemic circulation and is effective once inside the cell, we utilize best-in-class chemical modifications. This includes backbone modifications, such as phosphorothioate (PS) linkages, to protect against nuclease degradation, and strategically placed sugar modifications, such as 2′-O-methyl (2′-OMe) and 2′-fluoro (2′-F) nucleosides, to enhance the molecule's overall stability, binding affinity, and metabolic profile. These modifications are essential for achieving robust and sustained gene silencing.
The chemical linker connecting the biantennary GalNAc unit to the RNA payload is customized to ensure optimal spatial orientation for multivalent ASGPR binding. Our scaffolds are designed to maximize the efficacy of endosomal release, the rate-limiting step in GalNAc-mediated delivery, ensuring sufficient payload reaches the cytoplasm to engage the RNA-induced silencing complex (RISC) for gene knockdown. We offer tailored linker chemistries that are compatible with both siRNA and ASO formats, providing flexibility for diverse therapeutic strategies.
The biantennary GalNAc-RNA delivery service provides complete end-to-end support for developing liver-targeted nucleic acid therapeutics. We offer:
Full design services for both siRNA and ASO payloads, optimizing GalNAc attachment location and linker length to suit the specific oligonucleotide chemistry and desired pharmacological profile.
Access to a broad range of nucleotide modifications (2'-OMe, 2'-F, LNA, PS) for tuning pharmacokinetics, pharmacodynamics, and nuclease stability.
Production capabilities range from milligrams for exploratory research to multigram quantities for preclinical research, all manufactured with chemically defined precision.
Generation of detailed analytical and stability reports to support IND-enabling studies.
Selection of the most effective RNA sequence (siRNA or ASO) against your target mRNA, informed by in-house prediction algorithms and chemical modification design (e.g., 2'-F/2'-OMe incorporation, PS backbone placement) to maximize activity and stability.
Scalable, high-fidelity synthesis of the chemically modified RNA sequence using automated solid-phase phosphoramidite chemistry, ensuring high purity and definition of the final product.
Dedicated synthesis of the proprietary biantennary GalNAc cluster and functionalization with appropriate chemical handles (e.g., via customized tetraethylene glycol linkers) for subsequent conjugation to the oligonucleotide.
Covalent coupling of the activated biantennary GalNAc ligand to the oligonucleotide sequence, typically at the 3' end of the sense strand of siRNA or the 3' end of the ASO, followed by controlled cleavage and deprotection.
Rigorous purification via techniques such as anion exchange and reverse phase HPLC to achieve the required purity (>95%), followed by comprehensive QC, including mass spectrometry (MS) for identity confirmation and endotoxin testing, ensuring a clinical-ready product.
Optional service for cell culture testing to evaluate the conjugate's binding affinity to ASGPR and in vitro gene silencing potency in hepatocyte cell lines before resource-intensive in vivo studies.
Journal: Frontiers in Pharmacology
DOI: 10.3389/fphar.2022.1090237
Published: 2022
IF: 4.8
Results: This comprehensive review article explores the significant therapeutic potential of GalNAc-conjugated siRNAs as a leading platform for RNAi therapy. The authors detail the mechanism by which these conjugates, leveraging the high-affinity binding of the GalNAc ligand to the ASGPR abundantly expressed on hepatocytes, enable targeted delivery to the liver. They highlight the importance of specific chemical modifications to the siRNA backbone, such as 2'-OMe and 2'-F substitutions, which enhance metabolic stability and potency while minimizing off-target effects. The piece underscores the clinical success of several approved GalNAc-siRNA therapeutics, including givosiran, inclisiran, and lumasiran, which treat rare liver-associated diseases like acute hepatic porphyria, hypercholesterolemia, and primary hyperoxaluria type 1. Despite these advancements, the review also critically addresses persistent challenges, particularly the inefficient endosomal escape of siRNAs into the cytoplasm, which remains a major rate-limiting step for efficacy. The authors conclude by comparing GalNAc conjugates to other delivery systems like lipid nanoparticles (LNPs) and express optimism that ongoing research into novel chemistries and delivery strategies will further expand the application of this promising technology for treating a wider range of genetic disorders.
Protein Synthesis Disorders
Using GalNAc-ASO conjugates to modulate the production of specific secreted or intracellular proteins, such as those involved in Transthyretin-mediated amyloidosis.
Detoxification Pathway Modulation
Precisely regulating the expression of enzymes or transporters in the liver that are crucial for detoxification processes, but may be linked to specific toxicities or drug metabolism issues.
Custom Biomarker Research
Utilizing the platform for in vivo research to validate novel liver-specific gene targets quickly and accurately, accelerating the target identification phase of drug discovery.
Gene Therapy Optimization
Serving as a temporary liver-detargeting or expression control tool to improve the safety profile and manage the systemic distribution of viral or non-viral gene therapy vectors.
Unparalleled Hepatocyte Specificity
The GalNAc ligand targets the ASGPR, a receptor expressed almost exclusively on hepatocytes in the liver, minimizing off-target activity and potential systemic side effects.
Chemically Defined Composition
Every batch of our biantennary conjugate has a precise and known chemical structure, which minimizes batch-to-batch variability compared to multi-component systems.
Superior Pharmacokinetic Profile
The small, defined structure of the GalNAc conjugate allows for rapid systemic distribution and efficient capture by the ASGPR, contributing to a longer duration of action and enabling less frequent dosing regimens.
Versatile Payload Compatibility
The platform is optimized for both small interfering siRNA and ASO payloads, allowing maximum flexibility in your gene-modulating mechanism of choice.
The team at CD BioGlyco delivered our complex biantennary GalNAc-ASO conjugate ahead of schedule. The purity was exceptional, and the detailed QC report gave us complete confidence. The in vivo study confirmed a rapid, liver-specific knockdown, perfectly matching the published 5-10 fold potency enhancement we were targeting. Their understanding of divalent chemistry is truly expert-level, saving us critical time and resources in our development pipeline.
— Dr. K. Singh, Senior Research Scientist, Translational Medicine Department
Switching to CD BioGlyco for our GalNAc synthesis was a game-changer. The simplicity of their biantennary approach made scale-up significantly more predictable and cost-effective compared to our previous LNP strategy. The consistent, high-yield product allowed us to move into our toxicology studies with high confidence in the material's integrity and defined structure.
— Manager, L., Head of Preclinical Development, Rare Disease Therapeutic Group
We had a challenging target that required unique chemical modifications to our siRNA. CD BioGlyco's ability to integrate the 2'-F/2'-OMe chemistry with their divalent GalNAc linker was seamless. The resulting conjugate showed robust and sustained knockdown in our chronic liver disease model, validating their expertise in complex oligonucleotide engineering. Highly recommend their bespoke design service.
— Dr. M. Chen, Director, Hepatology Research Division
Custom synthesis of chemically stabilized antimiR oligonucleotides, often used for upregulating gene expression via microRNA antagonism, fully compatible with our GalNAc conjugation.
Production of high-purity, modified mRNA encoding reporter proteins. This is an essential tool for rapidly validating transfection/delivery efficiency in vitro and in vivo before committing to a therapeutic payload.
Manufacturing of long, complex saRNA constructs. While typically LNP-delivered, we can assist with the synthesis of the RNA payload for next-generation vaccine or protein-replacement strategies.
Specialized synthesis of various transfer RNA molecules and their derivatives for non-standard applications in translational control and synthetic biology research.
CD BioGlyco's biantennary GalNAc-RNA delivery service provides the critical combination of high-precision liver targeting, scalable manufacturing, and proven in vivo potency that your therapeutic program requires. By choosing our optimized divalent system, you gain access to an efficient, clinically validated technology for developing next-generation therapeutics against chronic and rare liver diseases. Our expert team is ready to apply our high-end chemistry and profound biological expertise to your most challenging targets. Contact us!
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