GalNAc-siRNA Conjugates

Among RNA therapeutics, RNAi technology has become an enticing platform for gene silencing accuracies, providing a rich treatise of prospective procedures for human diseases. However, efforts to translate siRNA from the bench to the bedside have been hampered by the daunting obstacle of effective delivery to target cells. The seemingly insurmountable barrier to liver hepatocytes has been overcome in recent years by the development of N-acetylgalactosamine (GalNAc)-siRNA conjugates, which provide a breakthrough method for targeted delivery to liver hepatocytes in a manner heretofore unmitigated. BOC Sciences promises to offer you with GalNAc-siRNA conjugation services to help you conduct further research on GalNAc-siRNA conjugates and explore their mores omnics capabilities, the working mechanism as well as their potential therapeutic profiles.

N Acetylgalactosamine (GalNAc)

GalNAc refers to N Acetylgalactosamine (GalNAc), which is an amino sugar derivative of galactose. It has potential as a targeting ligand in antisense oligonucleotides (ASO) and siRNA therapeutics. The high affinity recruitment of hepatocytes is achieved through the foundational use of GalNAc in GalNAc-siRNA conjugates for the Asialoglycoprotein receptor (ASGPR) which is highly expressed by hepatocytes. GalNAc has unusual structural characteristics that make it an able ligand for ASGPR recognition, which in turn enables swift cellular uptake and intracellular distribution of siRNA payloads.

What is GalNAc siRNA Conjugate?

GalNAc-siRNA conjugates represent a truly novel class of RNA therapeutics enabling liver hepatocyte-specific delivery of small-interfering RNA (siRNA) payloads at an unprecedented level of efficacy. In vitro, and also in vivo,GalNAc conjugated multivalent siRNA is more potent than siRNA alone and theoretically at about the same concentrations of GalNAc could dose about 10x less of siRNA when given as just siRNA in a water-soluble delivery vehicle. The GalNAc-siRNA conjugates have therefore provided a convenient means for siRNA drug delivery to the liver and have significantly enhanced tissue-specific delivery and efficacy in ASO and siRNA therapeutics. Encapsulated in cleverly designed N-acetylgalactosamine (GalNAc) conjugates, which specifically target the highly expressed Asialoglycoprotein receptor (ASGPR) of hepatocytes, these conjugates offer great promise for the treatment of a variegated spectrum of diseases ranging from metabolic disorders, to viral infections and beyond.

GalNAc Receptor

GalNAc-siRNA conjugates rely on the activity of ASGPR, which is the transmembrane lectin receptor highly expressed on hepatocytes. ASGPR that can effectively clear substrates from the blood via a a receptor-mediated endocytosis processes with broad application across species. Has high affinity for GalNAc ligands; upon ligand binding, triggers receptor-mediated endocytosis. Thus, it is considered as an optimal liver cell-specific candidate receptor for the targeted drug delivery system. Thereby, susceptible for GalNAc dependent receptor-mediated endocytosis through association with ASGR. Exploiting this natural liver cell selective targeting mechanism, GalNAc conjugates have made it possible to efficiently and precisely deliver therapeutic payloads to the liver, rendering them invaluable tools for the inventions of numerous effective disease management approaches.

BOC Sciences' GalNAc-siRNA Conjugates Services

BOC Sciences offers a wide spectrum of GalNAc-siRNA conjugates services including design, synthesis, characterization and preclinical evaluation. This platform utilizes cutting-edge nucleic acid chemistry and drug delivery technologies provided by our multidisciplinary team of experts to develop customized, individually tailored GalNAc-siRNA conjugates unmatched in precision and efficacy. Our end-to-end solutions from target selection through to preclinical validation provide clients the agility and efficacy required to accelerate their RNA therapeutic programs.

siRNA Design & GalNAc Choosing

Here, we start our journey by focusing on thoughtfully engineered strategies to enhance the potency, specificity, and stability of GalNAc-siRNA conjugates. Using cutting-edge computational modeling and structural biology techniques, our team is able to determine target genes, and logically infer the siRNA sequences optimal for silencing a particular disease-associated transcript. We further iterate on the chemical structure and conjugation strategy of GalNAc-siRNA conjugates to hone in on the right balance of therapeutic efficacy and safety.

Custom Synthesis & Conjuction Service

As an expert in synthetic chemistry and nucleic acid synthesis, BOC Sciences has a strong synthetic strength that allows to synthesize GalNAc-siRNA conjugates with efficient and accurate selective chemical composition and purity. With those aforementioned synthesis platforms, we can manufacture conjugates of the highest quality at scale and sufficient to support discovery and development preclinical. Rigorous quality control measures ensure the integrity and reproducibility of synthesized GalNAc-siRNA conjugates, laying the foundation for reliable therapeutic outcomes.

Figure 1. Schematic diagram of the synthesis of GalNAc-siRNA conjugates. (L, Zhang.; et al, 2022)

Characterization of GalNAc-siRNA Conjugates

GalNAc-siRNA conjugates must be well characterized in view of their physicochemical properties, stability, and pharmacokinetic profiles for evaluation. We use mass spectrometry, high-performance liquid chromatography (HPLC), and gel electrophoresis to characterize the synthesized conjugates comprehensively at BOC Sciences. Through defining critical quality attributes such as conjugate purity, molecular weight and binding affinity, we confirm the strength and reliability of GalNAc-siRNA conjugates across a range of formulations and lots.

Preclinical Evaluation & Analysis

Safety, efficacy, and pharmacokinetic evaluation of novel GalNAc-siRNA conjugates are carried out using preclinical rodent studies prior to translation into humans. Furthermore, BOC Sciences can provide a series of Preclinical Services, such as in vitro cell-based assays, animal pharmacokinetics studies, and efficacy evaluations in disease models.
With design, synthesis, and characterization, BOC Sciences provides a full spectrum of GalNAc-siRNA conjugates services, including preclinical evaluation, customization, and regulatory support. Together with our scientific community, innovative spirit, and collaboration with our clients, we strive to be a reliable partner in the evolution of precision medicine as facilitated by RNA therapeutics.

Why Choose BOC Sciences?

• Premium Raw Materials: We are delivered only the best raw materials to meet the high-quality standards of our products.
• Experienced Experts: With years of industry experience, our team of experts is well-equipped to handle any project with precision and expertise. Our dedicated technical support team is available to provide guidance and assistance, ensuring that your project runs smoothly from start to finish.
• Strict QA & QC: We run stringent quality assurance and quality control practices at all stages of of our production process to ensure the inherent reliability of our products.
• Advanced Analytical Equipments: Our testing and analysis processes are highly accurate and reliable as we employ modern analysis equipments.
• 1 on 1 Customer Service: We pride ourselves on giving you the personal touch with customized customer service, individualized attention, and support to your various needs.
• Competitive Price: Despite our promise of quality you may trust in competitive price to enable our production reach wide range of audience.
• Fast Delivery: We understand the importance of timely delivery, and our efficient logistics ensure that your products are delivered quickly and efficiently to meet your deadlines.

Case Study

Case study 1: Mitigation of Rat Hepatotoxicity in GalNAc-Conjugated siRNAs Selection

Figure 2. H&E staining of liver sections collected at necropsy. (Janas, M.M.; et al, 2018)

Small interfering RNAs (siRNAs) with trivalent N-acetylgalactosamine (GalNAc) ligand are under investigation in clinical trials for diverse indications. The selection process involves assessing the toxicity of lead compounds in rats at exaggerated doses. GalNAc-siRNAs exhibiting rat hepatotoxicity are excluded from further clinical development. This case focuses on investigating and addressing rodent hepatotoxicity associated with GalNAc-conjugated siRNAs selection. Rats were exposed to supratherapeutic doses of GalNAc-conjugated siRNAs. Evaluation focused on hepatotoxicity mechanisms, including RNAi-mediated off-target effects, chemical modifications, and disruption of RNAi pathways. Seed-pairing modulation with a thermally destabilizing chemical modification was employed to mitigate off-target effects. Rodent hepatotoxicity primarily stemmed from RNAi-mediated off-target effects rather than chemical modifications or RNAi pathway disruptions. Modulating seed-pairing using a thermally destabilizing chemical modification significantly enhanced the safety profile of GalNAc-siRNAs in rats. RNAi-mediated off-target effects contribute substantially to rat hepatotoxicity associated with GalNAc-conjugated siRNAs. Modulating seed-pairing with a thermally destabilizing chemical modification offers a promising strategy to mitigate off-target effects and enhance safety. This approach may reduce the occurrence of hepatotoxic siRNAs across different species, thus improving the safety profile of GalNAc-conjugated siRNAs for clinical development.

FAQ

1. What is GalNAc used for?

The role of GalNAc, N-acetylgalactosamine, is extensively described for most species in biology. Used to glycendate proteins commonly These additions are capable of altering the structure and function of proteins to regulate cellular signaling, adhesion, and various other central cellular processes. GalNAc also functions in a range of important biological processes from cell-to-cell recognition, immune response to development.

2. What is the receptor for GalNAc?

The receptor for GalNAc is the asialoglycoprotein receptor (ASGPR). It is primarily found on the surface of hepatocytes (liver cells). ASGPR specifically recognizes and binds to glycoproteins containing terminal galactose or N-acetylgalactosamine residues. This receptor plays a crucial role in the clearance of glycoproteins from the circulation and in the internalization of certain therapeutic agents targeted to the liver.

3. What are the siRNA drugs?

siRNA drugs are a group of drugs that use siRNAs. Such molecules are able to be tuned to target the expression of specific genes of interest, and thereby have the potential to over ride related disease pathologies. SiRNA therapeutics accomplish the repression of genes encoding disease targets, at the post-transcriptional level, by engaging the RNA interference (RNAi) pathway, thereby diminishing or abating the pathological consequences of their overexpression.

4. Is GalNAc a glycosaminoglycan?

No, GalNAc is not a glycosaminoglycan (GAG) No, it actually a monosaccharide, N- acetylgalactosamine. These proteoglycans, or matrix proteins with covalently bonded sugar chains, are made up of glycosaminoglycans or unbranched polymeric chains of repeating disaccharide units, each amino sugar with an uronic acid. GAGs also play a role in the ECM where they are constituents and modulators of biological processes such as cell signaling, tissue morphogenesis, and lubricating articulations.

5. What is the structure of GalNAc-siRNA?

A GalNAc-siRNA conjugate is a form of a GalNAC-siRNA in which the GalNAc molecule is linked to the siRNA molecule, usually at the 3′ end of the sense strand. This conjugate allows specific binding to hepatocytes because GalNAc attaches to asialoglycoprotein receptor on their cell surface. The siRNA molecule is composed of a double-stranded form of RNA, with the antisense strand guiding mRNA cleavage or translational repression by the RNA-induced silencing complex..

6. What does GalNAc bind to?

GalNAc binds to the asialoglycoprotein receptor (ASGPR). This receptor is predominantly found on the surface of hepatocytes (liver cells). ASGPR specifically recognizes and binds to glycoproteins containing terminal galactose or N-acetylgalactosamine (GalNAc) residues. This interaction plays a crucial role in the clearance of glycoproteins from the circulation and in the internalization of certain therapeutic agents targeted to the liver

References

1. Zhang, L.; et al. The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates. Sec. Drug Metabolism and Transport. 2022, 13.
2. Janas, M.M.; et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nature Communications. 2018, 9: 723.

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