How to find the chemical modification of Olpasiran?

Olpasiran, a promising therapeutic agent, is a small interfering RNA (siRNA) developed by Arrowhead Pharmaceuticals. This innovative medication targets apolipoprotein C-III (APOC3), a protein involved in lipid metabolism, and is specifically indicated for the treatment of hypertriglyceridemia, a condition characterized by elevated levels of triglycerides in the blood. Hypertriglyceridemia is a significant risk factor for cardiovascular diseases and pancreatitis, making effective treatments crucial for patient health.

Summary of Research Progress of Olpasiran

The research progress of Olpasiran has been marked by significant advancements and milestones. Mechanistically, Olpasiran operates through RNA interference (RNAi), a natural cellular process that can silence specific genes. By targeting the mRNA of APOC3, Olpasiran reduces the production of APOC3 protein, which plays a key role in the regulation of triglyceride-rich lipoproteins. This reduction in APOC3 levels leads to decreased triglyceride levels, thereby lowering the risk of cardiovascular events and pancreatitis. This targeted approach addresses the root cause of hypertriglyceridemia, offering a more comprehensive and sustainable treatment option compared to traditional lipid-lowering therapies.

Olpasiran has not yet received regulatory approval, but it is currently in advanced stages of clinical development. The drug has shown promising results in early-phase clinical trials, demonstrating significant reductions in triglyceride levels and favorable safety profiles. Arrowhead Pharmaceuticals has initiated Phase III trials to further evaluate the efficacy and safety of Olpasiran in larger patient populations. These trials are expected to provide robust data to support potential regulatory submissions in the coming years.

Globally, the competition in the hypertriglyceridemia treatment market is intense, with several established and emerging therapies. Traditional treatments include statins, fibrates, and omega-3 fatty acids, which are widely used but may have limitations in terms of efficacy and side effects. Olpasiran, with its novel mechanism of action and targeted delivery, offers a unique and potentially superior treatment option. The drug's ability to achieve sustained reductions in triglyceride levels with a less frequent dosing schedule makes it an attractive alternative for patients and healthcare providers.

Sequence Information and Characteristics of Olpasiran

The sequence information and characteristics of Olpasiran are essential to understanding its mechanism of action and therapeutic potential. Olpasiran is a chemically modified siRNA that targets the mRNA of APOC3. The siRNA is designed to be a double-stranded RNA molecule, each strand approximately 21 nucleotides long. The sequence of the siRNA is meticulously engineered to ensure high specificity and affinity for the target mRNA, minimizing off-target effects and maximizing therapeutic efficacy. The antisense strand of the siRNA hybridizes with the APOC3 mRNA, leading to its degradation and silencing of the APOC3 gene.

One of the key features of Olpasiran is its conjugation to a trivalent N-acetylgalactosamine (GalNAc) ligand, which facilitates liver-specific delivery. The GalNAc-siRNA conjugate is recognized by the asialoglycoprotein receptor (ASGPR) on hepatocytes, enabling efficient uptake and intracellular processing. This targeted delivery system ensures that the siRNA reaches its intended site of action, the liver, where APOC3 is predominantly expressed. The GalNAc conjugation also enhances the stability and bioavailability of the siRNA, allowing for a more potent and durable therapeutic effect.

Chemical Modification and Action of Olpasiran

The chemical modifications of Olpasiran further enhance its stability and efficacy. The siRNA component undergoes several modifications, including 2'-O-methoxyethyl (MOE) substitutions on the ribose sugar of certain nucleotides. These modifications increase the resistance of the siRNA to degradation by nucleases in the bloodstream, thereby extending its half-life and improving its stability. Additionally, the GalNAc conjugation improves the solubility and pharmacokinetic properties of the siRNA, allowing for a more stable and effective therapeutic molecule.

The action of Olpasiran is mediated through the RNA interference (RNAi) pathway. Once inside the hepatocytes, the GalNAc-siRNA conjugate is processed by the RNA-induced silencing complex (RISC). The passenger strand of the siRNA is degraded, while the guide strand remains bound to the RISC. The guide strand then hybridizes with the complementary APOC3 mRNA, leading to its cleavage and degradation. This process effectively silences the APOC3 gene, reducing the production of APOC3 protein and preventing the formation of triglyceride-rich lipoproteins. The reduction in APOC3 levels is sustained over time, providing long-lasting therapeutic benefits and lowering the risk of cardiovascular events and pancreatitis.

Summary and Prospect

In summary, Olpasiran represents a significant breakthrough in the treatment of hypertriglyceridemia. Its targeted mechanism of action, involving the silencing of APOC3 mRNA, offers a novel and effective approach to managing this condition. The drug's favorable safety profile, combined with its convenient dosing schedule of once-every-six-months subcutaneous injections, makes it an attractive option for patients with hypertriglyceridemia. With ongoing Phase III trials and strong preclinical and early-phase clinical data, Olpasiran is poised to play a crucial role in the future of hypertriglyceridemia treatment. Ongoing research and development efforts aim to further optimize the drug's therapeutic potential and explore its use in other related conditions, opening up new possibilities for patients suffering from lipid disorders and cardiovascular diseases. The success of Olpasiran not only highlights the potential of RNAi technology but also paves the way for the development of similar therapies for a wide range of metabolic and genetic disorders.

How to find the chemical modification of all siRNAs?

In Patsnap Bio, you can find the sequence and latest research and development advances of all siRNAs.

Taking Olpasiran as an example, first click on the Drug/Gene Index on the Patsnap Bio homepage. Here you can search for sequence information by drug and gene names. Enter ' Olpasiran ' in the search box and click to view the details. On the details page, you can find the basic information and research progress of Olpasiran.

Click "View all related sequences" below the sequence information to search for and retrieve all biological sequences similar to this information. 

Clicking on the sequence name will provide you with all the basic information of that sequence.

Additionally, a visual diagram of the sequence's chemical modifications is available for immediate access.

Patsnap Bio helps you turn weeks into minutes with cutting-edge AI-enabled tools built to master the complexities of sequence retrieval and automate IP analysis with precision and ease.