GalNAc-ASO Conjugation

As a leading CRO agency, BOC Sciences offers customized GalNAc-ASO conjugation services to support customers' R&D needs. With our expertise in drug conjugation, we are committed to providing high-quality and reliable services to accelerate the development of novel ASO-based therapeutics.

Why conjugated ASO?

Antisense oligonucleotides (ASO) are single-stranded oligonucleotides, usually containing 15-25 nucleotides, that bind to the target RNA through the principle of base pairing to regulate the function of the target RNA. ASO can regulate gene expression by blocking RNA translation, promoting RNA degradation, or altering RNA splicing, and is widely used in the treatment of genetic diseases, cancer, and viral infections.

What is GalNAc-ASO Conjugation?

GalNAc (N-acetylgalactosamine) conjugation modification is one of the most commonly used small nucleic acid drug delivery systems. N-acetylated galactosamine (GalNAc) is covalently conjugated to the 3' ends of the RNA sense strand of different sequences in a trivalent manner to form polysaccharide-RNA monoconjugates. GalNAc is a targeted ligand for the sialic acid receptor (ASGPR), which has a high affinity for liver surface cells and rapid internalization ability. GalNAc binds to ASGPR on the surface of hepatocytes and enters the cell to form endosomes, thereby enabling efficient delivery of ASO.

Fig.1 A GalNAc-ASO Conjugation connected with cholesterol. (Wada Fumito, et al., 2018)

Advantage of GalNAc-ASO Conjugation

Targeting: GalNAc-ASO conjugation can significantly enhance the tissue targeting specificity of the liver, and the drug efficacy is increased by 10 times. This means that the drug is able to reach the target site more accurately, which improves the effectiveness of the treatment.

Route of Administration: GalNAc-ASO conjugation can be administered by subcutaneous injection, avoiding renal filtration problems that can result from direct intravenous injection. This not only improves patient comfort but also reduces potential side effects.

High cell uptake: With the help of the cell's intrinsic endocytic pathway, GalNAc-ASO conjugation has a higher entry efficiency and is able to enter the target cell more efficiently to act.

Safety: GalNAc-ASO conjugation is safer than nano delivery systems. This means that it enables efficient delivery while minimizing risk to patients.

The mechanism of GalNAc-ASO Conjugation

GalNAc-ASO rapidly enters the cell to form endosomes by binding to ASGPR receptors on the surface of liver cells. Subsequently, ASO is released and binds to the target RNA to regulate gene expression and achieve therapeutic effects.

Application of GalNAc-ASO Conjugation

GalNAc-ASO conjugation technology has shown great potential in the treatment of a variety of liver-related diseases, including but not limited to the following areas:

Hereditary liver disease: GalNAc-ASO conjugation technology is able to target and regulate the RNA of mutant genes to precisely adjust the expression of abnormal genes. This mechanism helps to correct pathological conditions due to genetic mutations, such as the treatment of inherited liver diseases such as hepatic liposis or hepatic metabolic defects.

Liver cancer: In the treatment of liver cancer, GalNAc-ASO conjugation technology exerts anti-tumor effects by inhibiting the expression of oncogenes or activating tumor suppressor genes. This technology can specifically intervene with key molecules associated with cancer development, thereby effectively inhibiting tumor growth and spread, providing a promising therapeutic strategy.

Viral hepatitis: GalNAc-ASO conjugation has also shown therapeutic potential for viral hepatitis. By targeting viral RNA, GalNAc-ASO is able to effectively inhibit viral replication. This precise intervention against viral RNA not only improves the specificity of the treatment, but also reduces the side effects on the host cells and improves the treatment effect.

Study of GalNAc-ASO Conjugation

Pelacarsen (AKCEA-APO(a)-LRx) is a liver-specific GalNAc-ASO conjugation directed against apolipoprotein(a)[Lp(a)]. The drug significantly reduces lipoprotein (a) levels by binding to the mRNA of Lp(a) and inhibiting its expression. Pelacarsen is primarily used to treat patients with hyperlipoprotein(a)emia, especially those at high risk of cardiovascular disease. Data from the phase 2 clinical study showed that Pelacarsen could reduce lipoprotein (a) by 80%, and the dose of 80 mg/month could reduce lipoprotein (a) levels to less than 50 mg/dL in 98% of patients. Pelacarsen is expected to be the first GalNAc-ASO lipid-lowering drug to effectively reduce Lp(a) levels, providing more innovative treatment options for clinical disease prevention and treatment and cardiovascular health management.

Available GalNAc-ASO conjugate services

BOC Sciences offers a comprehensive range of GalNAc-ASO conjugation services, including design, synthesis, and characterization. Our services cover the following areas:

Customized design: Design sequence-specific antisense oligonucleotides (ASOs) according to the specific needs of customers, and optimize the GalNAc conjugating strategy to ensure that ASO can efficiently target the liver.

Synthesis and purification: GalNAc-ASO conjugates are prepared by efficient synthesis methods, and the high purity and yield of the products are guaranteed through advanced purification technology. This step is critical to ensure that the final product has the best possible biological activity and safety.

Characterization and validation: Detailed characterization and validation of synthetic GalNAc-ASO conjugates using a variety of techniques. These include mass spectrometry, high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and other methods to confirm its structure, purity and function. These characterization methods can ensure that the product meets the expected requirements in terms of quality and function, thus guaranteeing its effectiveness and reliability in practical applications.

BOC Sciences is committed to helping customers achieve breakthroughs in the field of new drug discovery through advanced GalNAc-ASO conjugation technology.

FAQ

1. What is GalNAc-ASO conjugation?

GalNAc-ASO conjugation is a technique that binds N-acetylgalactosamine (GalNAc) to an antisense oligonucleotide (ASO). GalNAc can specifically recognize receptors on hepatocytes, thereby precisely delivering ASO to the liver for regulation or inhibition of gene expression.

2. What are the main applications of GalNAc-ASO conjugation technology?

This technique is mainly used for liver-related diseases, including hereditary liver diseases (such as hepatic liposis), liver cancer, and viral hepatitis. By regulating gene expression, inhibiting oncogene or viral RNA replication can achieve therapeutic effects.

3. How safe is the GalNAc-ASO conjugation technology?

GalNAc-ASO conjugation technology has a high safety profile because it specifically targets the liver and avoids the exposure of non-targeted tissues. Compared with the nano delivery system, it is less toxic to non-target cells and has fewer side effects.

4. What is the clinical outlook for GalNAc-ASO conjugation technology?

This technology has shown good results in preclinical research and early clinical trials, especially in the treatment of liver diseases. Its precise targeting ability and effective gene regulation effect make it an important tool for gene therapy for liver diseases. With further research and technology optimization, GalNAc-ASO conjugation technology is expected to achieve greater breakthroughs in clinical applications.