MicroRNAs (miRNAs) are pivotal regulators of gene expression, and their dysregulation is a hallmark of numerous hepatic pathologies, including metabolic disorders and hepatocellular carcinoma (HCC). Anti-microRNA oligonucleotides (AntimiRs) offer a powerful strategy to neutralize these pathogenic miRNAs; however, their clinical success depends entirely on efficient, tissue-specific delivery. At CD BioGlyco, we provide a specialized GalNAc-antimir delivery service that leverages the high-affinity interaction between N-acetylgalactosamine (GalNAc) and the asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes. By conjugating trivalent GalNAc clusters to chemically optimized antimiRs, we enable precise liver targeting, enhanced cellular uptake, and prolonged therapeutic durability.
As a cornerstone of our Therapeutic Nucleic Acid Development Platform, the Therapeutic Oligonucleotide Delivery Service at CD BioGlyco offers a comprehensive suite of solutions tailored specifically to GalNAc-antimiR development. We recognize that every miRNA target presents a unique biological challenge, characterized by distinct expression profiles and secondary structures. Consequently, successful inhibition requires a bespoke approach that harmonizes ligand placement, chemical modification patterns, and sequence architecture to achieve optimal therapeutic outcomes.
Our specialists collaborate with you to define the target miRNA and design the antimiR sequence. We utilize bioinformatic tools to predict off-target risks and optimize LNA/PS modification patterns for maximum stability and affinity.
We synthesize high-quality trivalent GalNAc ligands, such as GalNAc-L96. We ensure the ligands are activated for seamless integration during the oligonucleotide synthesis process.
Using state-of-the-art synthesizers, the antimiR is synthesized with the GalNAc moiety attached directly via a specific linker. This ensures a defined, single-component molecular entity with precise stoichiometry.
The crude conjugate undergoes rigorous purification using high-performance liquid chromatography (HPLC). We confirm the identity and purity of the GalNAc-antimiR via mass spectrometry (MS) and capillary electrophoresis (CE).
We validate the targeting efficiency by performing binding assays with recombinant ASGPR and uptake studies in primary hepatocytes or HepG2 cell lines to ensure the conjugate reaches its intracellular destination.
Our team facilitate preclinical testing, evaluating the biodistribution, liver accumulation, and target miRNA knockdown in animal models to confirm therapeutic efficacy.
DoI: 10.3390/pharmaceutics13060817
Journal: Pharmaceutics
IF: 5.5
Published: 2021
Results: This study focuses on developing GalNAc-conjugated tiny LNA anti-miRNA-122 antisense oligonucleotides to address the challenges of clinical anti-miRNA antisense oligonucleotides (ASOs) development. The most potent construct, tL-5G3, exhibits an ED50 of ~12 nmol/kg, 300-500 times more potent than the unconjugated tiny LNA. GalNAc conjugation improves the poor pharmacokinetics of tiny LNAs, enhancing liver targeting and reducing renal accumulation and toxicity. Key findings show GalNAc should be linked to the 5′ terminus via a biolabile phosphodiester bond, as tiny LNAs need nuclease digestion to release the parent molecule. In vivo studies confirm dose responsiveness, effective miR-122 inhibition, and cholesterol reduction. This strategy advances miRNA-targeted small ASO therapy, laying the groundwork for clinical applications.
Fig.1 Schematic illustration of the miRNA-122 detection method devised in this study. (Yamamoto, et al., 2021)
Metabolic Disorders
Our delivery platform ensures potent silencing of pathogenic miRNAs, facilitating the development of long-acting treatments for widespread chronic metabolic dysfunction.
Viral Hepatitis Research
This precision targeting disrupts viral replication and helps restore the host's innate immune response, providing a robust tool for developing curative anti-viral therapies.
Rare Genetic Liver Diseases
Targeting specific miRNAs involved in the regulation of enzymes related to rare hepatic disorders and orphan diseases. This service enables precise modulation of metabolic pathways, developing a highly specific therapeutic approach.
Chronic Liver Fibrosis
GalNAc-mediated delivery ensures these therapeutic antimiRs reach the liver effectively, offering a promising strategy to arrest or reverse the progression of chronic liver cirrhosis.
Exceptional Targeting Specificity
Our trivalent GalNAc ligands ensure nearly exclusive uptake by hepatocytes via the ASGPR, significantly reducing the required dose and mitigating off-target effects in non-hepatic tissues.
Superior Metabolic Stability
By combining GalNAc technology with advanced modifications like 2'-O-methyl (2'-OMe) and PS bonds, we provide conjugates that resist nuclease attack for weeks or months.
Well-Defined Molecular Entities
Our conjugates are single, homogeneous molecules. This simplifies chemical characterization, ensures batch-to-batch consistency, and streamlines the regulatory approval process.
Expert Technical Guidance
Clients benefit from our deep expertise in glycobiology and nucleic acid chemistry, ensuring that every project is optimized for the specific biological challenges of the liver.
"The GalNAc-antimiR conjugates showed remarkable liver specificity in our rodent models, far exceeding the performance of our previous delivery methods. Their technical expertise made the entire process seamless."
– B.S., Innovative Biotech Firm
"Working with CD BioGlyco's therapeutic nucleic acid platform has been a game-changer for our academic research into NASH. The purity of the LNA-modified conjugates was outstanding."
– D.G., Leading Research Institution
"The transition from small-scale screening to our larger preclinical studies was handled with professional precision and excellent communication."
– F.H., Pharmaceutical Company
CD BioGlyco is committed to advancing the field of liver-targeted miRNA therapy through our high-performance GalNAc-antimiR delivery service. By combining the precision of glycobiology with cutting-edge oligonucleotide chemistry, we empower our clients to overcome the challenges of delivery and unlock the full potential of antimiR therapeutics. Please feel free to contact us to help you design the optimal conjugate for your project.
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