Targeted delivery remains the cornerstone of effective oligonucleotide therapeutics, particularly for gene targets expressed in the liver. CD BioGlyco provides a cutting-edge solid phase-based GalNAc-RNA delivery service, utilizing advanced phosphoramidite chemistry to assemble triantennary GalNAc clusters directly onto the 5'-end of antisense oligonucleotides (ASOs). This approach leverages the high affinity of GalNAc for the asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes, facilitating efficient "free-uptake" without the need for complex lipid formulations. By integrating the conjugation process into automated solid-phase synthesis, we eliminate the need for laborious solution-phase steps or specialized pre-loaded supports, significantly accelerating the path from design to lead optimization.
Our platform is built upon high-efficiency phosphoramidite chemistry and the use of proprietary trebler scaffolds to ensure precise molecular architecture.
We utilize automated DNA synthesizers to sequentially couple trebler phosphoramidites, creating a branched scaffold directly on the solid support-bound oligonucleotide.
The resulting triantennary GalNAc cluster mimics natural ligands for the ASGPR, ensuring rapid internalization into liver cells.
Our technology allows for the introduction of negatively charged phosphodiester groups in the GalNAc tether, which can influence the internalization and metabolic profile of the conjugate.
5'-GalNAc conjugates synthesized via our platform are designed to be cleanly metabolized in the liver to liberate the potent parent ASO, acting as efficient hepatocyte-targeting prodrugs.
The sequence of interest is synthesized on a high-quality solid support using standard automated protocols to yield the support-bound ASO.
A trebler phosphoramidite solution is delivered to the solid support, initiating the coupling reaction to create the triantennary branching point.
The newly formed phosphite triester linkages are oxidized to stable phosphodiesters using specialized oxidation reagents for precise contact times.
GalNAc phosphoramidites are delivered in excess to the trebler-modified support, ensuring complete conjugation to all three branches of the scaffold.
A final oxidation step is followed by treatment with aqueous ammonia at controlled temperatures to cleave the conjugate from the support and remove protecting groups.
The final 5'-GalNAc-ASO conjugate is purified and thoroughly characterized using LC-MS analysis to confirm mass accuracy and UV purity.
Journal: Pharmaceutics
DOI: 10.3390/pharmaceutics16070938
Published: 2024
IF: 5.5
Results: In this study, the authors investigated a novel therapeutic strategy for hyperuricemia using GalNAc-conjugated small interfering RNA (siRNA) to specifically target xanthine oxidoreductase (XOR) in the liver. They designed and screened siRNAs targeting a homologous region of human and mouse XOR mRNA. After chemical modification for stability, the most effective siRNAs were conjugated to GalNAc for liver-specific delivery. The therapeutic efficacy of these GalNAc-siRNAs was evaluated in three different hyperuricemic mouse models. The results demonstrated that subcutaneous administration of GalNAc-siRNA significantly reduced plasma uric acid levels, decreased uric acid accumulation in the kidney, and alleviated renal inflammation and fibrosis, thereby protecting against kidney damage. Importantly, the treatment showed no hepatotoxicity or significant off-target effects, presenting it as a promising and safe strategy for hyperuricemia therapy.
Metabolic Disorder Research
Targeting hepatic genes involved in glucose and lipid metabolism, such as SRB-1, to develop treatments for metabolic syndrome and related conditions.
Hypercholesterolemia Therapeutics
Developing GalNAc-conjugated ASOs to inhibit targets involved in cholesterol transport and regulation, facilitating more effective management of high cholesterol levels.
NASH and NAFLD Drug Development
Developing targeted interventions for non-alcoholic steatohepatitis and fatty liver disease by delivering RNA therapeutics directly to the site of lipid accumulation.
Hypertriglyceridemia Treatments
Using our high-potency GalNAc platform to target hepatic enzymes responsible for triglyceride synthesis and secretion, offering a potent alternative to current systemic therapies.
Simplified Synthetic Route
By utilizing solid-phase phosphoramidite chemistry, we eliminate the need for multistep solution-phase synthesis of complex GalNAc clusters, reducing production time.
Enhanced Hepatocyte Delivery
Our GalNAc clusters increase ASO distribution to the liver by approximately 3-fold compared to unconjugated parent oligonucleotides, maximizing therapeutic impact.
Optimized Kidney Sparing
Conjugation through our platform results in significantly lower kidney tissue concentrations compared to unconjugated ASOs, potentially reducing off-target renal effects.
Clean Metabolic Profile
Our 5'-conjugated oligonucleotides are fully metabolized to the unconjugated parent ASO in the liver, ensuring predictable pharmacological activity.
The potency boost we saw in our hepatic targets after switching to CD BioGlyco's solid-phase GalNAc service was remarkable. The 50-fold increase in hepatocyte activity allowed us to progress our lead candidate much faster than anticipated.
— Dr. AL, Principal Scientist, Cardiovascular Research
The kidney-sparing effect of these conjugates is a game-changer for our safety assessments. We've seen a significant shift in tissue distribution that favors our therapeutic goals.
— Dr. PY, Department Head, Nucleic Acid Therapeutics
The 'free-uptake' capability of the CD BioGlyco GalNAc clusters in primary hepatocytes provides much more physiologically relevant data than traditional transfection methods. Highly recommended for liver-targeted programs.
— Dr. R.S., Head of Molecular Biology, Research & Development
CD BioGlyco's ability to provide high-purity GalNAc-ASO conjugates with a clean metabolic profile has been instrumental in our SAR studies. Their automated process ensures consistency that we couldn't find elsewhere.
— Manager, Drug Discovery, Metabolic Diseases
CD BioGlyco is your dedicated partner in advancing hepatocyte-targeted RNA therapeutics. Our solid phase-based GalNac-RNA delivery service combines scientific rigor with synthetic efficiency to provide you with the most potent and pure conjugates available. Contact us for more information and to discuss your project.
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