In recent years, the research and development and clinical treatment of small nucleic acid drugs have achieved many breakthrough results. It has become a new global investment outlet and a must-win for biopharmaceutical giants, and nucleic acid therapy has entered the fast lane.
Drugs made of small nucleic acids target mRNA in cells mostly through the mechanism of base complementary pairing, and serve the disease-treatment function by regulating protein expression. Traditional small molecule drugs and Antibody drugs mostly target proteins and targets are limited. The mechanism of small nucleic acid drugs targeting mRNA provides a large number of rich candidate targets for new drug research and development. Small nucleic acid drugs benefits from short R&D process, stability, high R&D success rate, difficult to build drug resistance, broad field of treatment. It is predicted that small molecules, antibodies, and small nucleic acid drugs will account for one-third of the new drug R&D technology pipeline in the future, and small nucleic acid drugs will trigger the third wave.
ASO acts on the translation from mRNA to protein, and is an undisputed leader in the discovery and use of small nucleic acid drugs. ASO is a synthetic short single-stranded oligonucleotide that regulates protein production through two pathways after entering the cell. The therapeutic areas of ASO drugs currently under research cover the central nervous system, cardiovascular, anti-infection and tumor, and more and more ASO-based therapies are being tested in clinical trials. Improvements in ASO drug delivery may change the treatment landscape of many diseases in the near future.
RNA interference (RNAi) is an ancient biological mechanism used to defend against foreign invasion. In theory, it can silence any disease-related gene in a sequence-specific manner, making small interfering RNA (siRNA) a promising treatment. If no protective delivery carrier exists, siRNA would have to be chemically manipulated to maintain stability in the bloodstream following parenteral injection.
SiRNA are artificially produced double-stranded short RNA molecules that can attach to AGO proteins to form RNA-induced silencing complexes (RISCs). One of its strands is broken down, and the other strand, in a similar process of complementary base pairing, binds and slices through the mRNA of the target gene, thereby blocking the expression of the target protein, for the very reason of curing associated diseases. It has high specificity.
The coupling with N-acetylgalactosamine (GalNAc) allows siRNA target organs to accumulate more efficiently and get absorbed into cells. Good siRNA design and optimal routes for administration are key to GalNAc-siRNA clinical translation. In addition, advances in backbone chemistry originally designed for ASO therapy have also been applied to siRNA therapy. Meanwhile, administration route directly influences clinical translation of GalNAc-siRNA conjugates and patient compliance. After 20 years of work, there are 5 siRNA drugs on the market. This milestone has been achieved because siRNA therapy has and will be transforming the treatment and management of human diseases. It can be given every quarter, or even every other year, and have the long-term therapeutic results.
Aptamer is a single stranded oligonucleotide, folded into a very special three-dimensional shape using In Vitro Screening. It will bind very specifically to any proteins, small molecules, metal ions, viruses, bacteria and even whole cells. Its high specificity and binding affinity can reach the level of antibodies. Compared with antibody drugs, nucleic acid aptamers have the advantages of small size, low immunogenicity, cell-free Chemical Synthesis, strong tissue penetration, easy modification and low cost. They have a wide range of drug application potential in disease diagnosis, treatment and prevention. However, its three-dimensional conformation depends a lot on pH, and its affinity also depends a lot on the structure of the solution. The FDA cleared the first aptamer drug, Pegaptanib, in 2004. It is an aptamer RNA of 29 Nucleotides, and the polyethylene glycol component at the 5’ end may extend its time of living in the human body. Pegaptanib binds to vascular endothelial growth factor (VEGF) via spatial positioning to inhibit angiogenesis in order to treat, so it’s created for wet age-related macular degeneration.
CpG ODNS can trigger immune regulation cascade reactions. CpG ODNS is a synthetic oligodeoxynucleotide (ODNS). It contains unmethylated cytosine guanine dinucleotide (CpG), which can simulate bacterial DNA to stimulate immune cells of many mammals, including humans. It can directly activate B cells and monocytes (macrophages and dendritic cells), and indirectly activate a variety of immune effector cells such as NK cells and T cells, enhancing their function and cytokine secretion. Enhance antigen processing and presentation. Induce Th1-type immune response, produce strong humoral and cellular immunity, enhance specific and nonspecific immune responses, and is expected to be used as an immunoprotectant and Vaccine Adjuvant in immunotherapy.
It can enhance protein transcription, which is opposite to the effect of siRNA. saRNA is a short double-stranded oligonucleotide with a chemical structure similar to siRNA, but the effect is opposite. saRNA works through a completely different RNA activation (RNAa) mechanism. The saRNA double strand first binds to the Ago2 protein in the cytoplasm, and then the complex enters the nucleus, binds to the gene promoter through the saRNA and recruits transcription-related proteins (PAF1 complex, RHA and RNA polymerase II, etc.), histones are modified (known modifications include Methylation, acylation and monoubiquitination), and finally gene expression is activated.
Acting on the translation process of mRNA to protein, miRNA is a class of naturally generated small non-coding RNA molecules that can be partially complementary to one or more mRNA molecules and downregulate gene expression through translation inhibition, mRNA shearing and deadenylation. There are problems such as poor specificity and easy to produce immune-related side effects.
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| X22-09-ZQ074 | Uridine 5'-triphosphate (UTP) sodium salt solution, 100 mM | >98% | Inquiry |
| X22-09-ZQ075 | Adenosine 5'-triphosphate (ATP) tris solution, 100 mM | >98% | Inquiry |
| X22-09-ZQ076 | Guanosine 5′-triphosphate (GTP) tris solution, 100 mM | >98% | Inquiry |
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The rapid development of small nucleic acid drugs depends largely on the progress of delivery technology. The delivery method and efficiency are the key to whether small nucleic acid drugs can enter cells and play a role. Small nucleic acid drugs face two major challenges in entering cells. One is that RNA exposed to the blood is easily degraded by RNase Enzymes in plasma and tissues; the other is that negatively charged RNA is difficult to cross the membrane and enter the cell. Although different RNA therapies may have different mechanisms of action, they must all avoid being cleared by non-target organs and must enter the correct tissue without triggering harmful immune responses.
According to the classification of different delivery technologies, it can be divided into naked RNA modification delivery technology, liposome nano-delivery technology, conjugated delivery system (small molecule ligands, antibodies and other molecules) and other types of delivery systems (such as polymer nanoparticle delivery system, extracellular vesicle delivery system). Among them, LNP and GaINac technologies are relatively mature. GaINac technology mainly targets the liver, and drug delivery systems targeting other organs are also expected to break through in the future.
At present, nucleic acid drug delivery vectors are mainly divided into viral and non-viral vectors. Viral vectors are widely used in gene therapy because they can effectively infect host cells. However, due to their immunogenicity, tumorigenicity, and limited loading capacity, they are relatively less used in nucleic acid drugs. In order to make up for the shortcomings of viral vectors, non-viral delivery vectors have become a new research direction, such as polymers and lipids (Liposomes or LNP); and nucleic acid drugs can be combined with specific ligands to enable them to target specific cells, such as GalNAc, peptides, antibodies, etc. Among them, LNP and GalNAc technologies are relatively mature. Currently available ASO drugs are heavily modified, so delivery vectors are not necessary, and siRNA is easily degraded, so vector delivery technology is mostly used.
LNP is one of the most studied and applied delivery systems for nucleic acid drugs. As early as 2018, the FDA approved the RNAi therapy Onpattro (patisiran) delivered using LNP technology for marketing. It encapsulates siRNA in lipid nanoparticles and delivers the drug directly to the liver through intravenous infusion to prevent the body from producing pathogenic proteins.
LNP has been widely used in the study of oligonucleotide drugs, especially ASO and siRNA. Liposomes include positive, neutral and negative liposomes, among which positive liposomes are usually used as delivery carriers because they are easy to bind to negatively charged nucleic acids, that is, they interact with negatively charged phosphate groups in nucleic acids through electrostatic forces to form Nanoparticles. This lipid complex can protect the genetic material from degradation and deliver it inside mammalian cells.
Compared with other types of nucleic acid drug delivery systems, LNP has many advantages, such as high nucleic acid encapsulation rate and effective cell transfection, strong tissue penetration, low cytotoxicity and immunogenicity, and more conducive to drug delivery. These advantages make LNP an excellent nucleic acid delivery system.
PNP is a synthetic branched histidine and lysine polypeptide copolymer (HKP). In aqueous solution, the amino group of lysine in the HKP polypeptide molecule and the phosphate group in the nucleic acid molecule are combined through ionic bond interactions (there are other interactions such as hydrophobic bonds between molecules) to self-assemble into nanoparticles of a certain size. Drug nanoparticles enter cells through endocytosis. In the endosome, due to the increase in acidity, the weakly alkaline histidine begins to protonate, which in turn causes the endosomal membrane to dissolve and release the small interfering nucleic acid molecules contained. In addition, PNP can deliver two siRNAs to the same cell in the same tissue, so it can target multiple pathways in cancer cells to prevent them from escaping treatment pressure.
GalNAc technology is the current mainstream small nucleic acid delivery technology. GalNAc is an amino sugar derivative of Galactose. Triantennary GalNAc has a high affinity with the asialoglycoprotein receptor (ASGPR) selectively expressed on hepatocytes, and can achieve specific binding. ASGPR delivers the corresponding ligand to hepatocytes through endocytosis. Therefore, it has a high liver targeting specificity, and the amount entering other tissue cells is very small. GalNAc is currently mainly used for the delivery of siRNA or ASO. It can form a conjugate with siRNA or ASO drugs, and use the binding ability between GalNAc and ASGPR specifically expressed by hepatocytes to accurately deliver drugs to the liver.
Small nucleic acid drugs, as drugs that target RNA and regulate gene expression or function, have three major characteristics: high specificity, durability, and curability. Currently, small nucleic acid drugs have shown promise in treating various diseases, especially genetic and rare diseases. There are also many candidate drugs under development for the treatment of common diseases such as cancer, cardiovascular disease, and viral infections. Of course, small nucleic acid drugs face challenges such as stability, biodistribution, cellular uptake, endosomal escape, and immunogenicity during drug delivery. At present, new drug research and development teams have developed various strategies to overcome these challenges, such as chemical modification, bioconjugation, and nanocarrier preparations.
