Introduction and Concepts of siRNA Drug (Oligonucleotides)

Background

By virtue of its unique technical characteristics, siRNA Drug has become the focus of attention in the field of new drug research and development in recent years, and is one of the most rapidly developing gene therapies at present. Compared with traditional small molecule drugs and antibody drugs, siRNA Drug can intervene from the source, with the advantages of fast target screening, high therapeutic efficiency, not easy to produce drug resistance, long-lasting effect, low toxicity, strong specificity, R & D success rate and so on, which is regarded as bringing the “in addition to small molecule drugs and antibody drugs” outside of the third wave of pharmaceuticals. The third wave of pharmaceuticals in addition to small molecule drugs and antibody drugs. 

However, as a new class of drug molecules, siRNA Drugs are polar, charged, and require chemical modifications and drug delivery systems to improve drug-forming properties, and thus have different pharmacological properties from chemical small molecules and antibody drugs, which poses a new challenge for the early development of siRNA Drugs.

Introduction of siRNA Drugs

siRNA Drugs, also known as Oligonucleotides (ONs), refer to drug-ready oligonucleotides typically 18-30 nt in length. Small RNA Drugs include small interfering RNA (siRNA), Antisense oligonucleotide (ASO), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), Aptamer, and Antibody-oligonucleic conjugates (AOC).

Current research focuses on three types of siRNA Drugs: ASO, siRNA and Aptamer. Different oligonucleotides have different mechanisms of action, and they play the role of inhibitors at different stages of pathogenesis. ASO and siRNA act at the level of target mRNA; Aptamer directly inhibits the activity of proteins involved in pathogenesis. Their common point is that they intervene in the expression of target genes to achieve the purpose of disease treatment.

Overall, the unique mechanism of action makes the small nucleic acid drugs have many advantages: high therapeutic efficiency, strong target specificity, low toxicity, wide range of therapeutic areas, etc., and compared with the small molecule drugs and antibody drugs, the small nucleic acid drugs have short research and development cycle, not easy to produce drug resistance, long-lasting effect, and high success rate of research and development, which is regarded as the third generation of pharmaceutical innovation technology that will promote the change of the pharmaceutical industry following the small molecule drugs and antibody drugs. More and more pharmaceutical companies have invested in the innovative research and development of siRNA Drugs.

Status of small nucleic acid drugs on the market

Approved Small Nucleic Acid Drugs:

• Antisense Oligonucleotides (ASOs): These single-stranded DNA or RNA molecules bind to specific mRNA sequences to inhibit translation or modify splicing. Notable ASOs include:
• Nusinersen (Spinraza): Approved for spinal muscular atrophy.
• Eteplirsen (Exondys 51): Targets Duchenne muscular dystrophy.
• Inotersen (Tegsedi): Treats hereditary transthyretin-mediated amyloidosis.
• Small Interfering RNAs (siRNAs): Double-stranded RNA molecules that promote the degradation of target mRNA.

Approved siRNA therapies include:

• Patisiran (Onpattro): The first FDA-approved siRNA drug, addressing hereditary transthyretin-mediated amyloidosis.
• Givosiran (Givlaari): For acute hepatic porphyria.
• Lumasiran (Oxlumo): Targets primary hyperoxaluria type 1.
• Aptamers: Short, structured nucleic acids that bind to specific proteins.
• Pegaptanib (Macugen): An aptamer approved for age-related macular degeneration.

Keywords: GalNAc-siRNA, siRNA Delivery, siRNA Escape, Liver Lysosomes, Hepatocyte Lysosomes, Tritosome, Lysosome Catabolism, Lysosomal Stability, Lysosomal Acid Phosphatase