In 1998, Andrew Fire and Craig Mello first revealed the mechanism of RNA interference in Caenorhabditis elegans, which led to them being awarded the Nobel Prize in 2006. Small nucleic acid drugs, as the clinical practice of a Nobel Prize-winning theory, represent a phenomenal technological revolution in disease treatment. In recent years, advances in delivery technologies have accelerated the development and commercialization of small nucleic acid drugs.
Currently, several small nucleic acid drugs have been approved and launched globally. Countries are competing intensively in technological innovation and platform development, production processes, scale-up, clinical trials, and approval processes. This has significant implications for breakthroughs in disease treatment and the development of precision medicine. Small nucleic acid synthesis, as the core underlying technology in the field of small nucleic acid drugs, shows tremendous potential.
Classification of Small Nucleic Acid Drugs
Small nucleic acid drugs are primarily classified into two main types based on the type of drug: Small Interfering RNA (siRNA) and Antisense Oligonucleotides (ASO).
The mechanism of action of siRNA involves the specific degradation of mRNA. Once the double-stranded siRNA enters the cell, it binds to the RNA-induced silencing complex (RISC). The double strand is separated, and one of the single strands guides RISC to bind to the target mRNA, catalyzing the cleavage of the ends complementary to the antisense strand of the siRNA. This results in mRNA degradation, downregulating protein expression and ultimately treating the related disease.
ASO can first complete its therapeutic mechanism by regulating the splicing of pre-mRNA. Incorrect pre-mRNA splicing can lead to a misfolded protein structure, affecting protein function and causing diseases. ASOs can bind to pre-mRNA, "masking" splicing signals, thereby causing the splicing machinery to selectively skip or retain certain sequences, correcting the translation reading frame to produce normal or functional proteins, thus achieving disease treatment. ASOs can also bind to target mRNA and induce endogenous RNase H1 to recognize the RNA-DNA duplex, catalyzing the degradation of mRNA and inhibiting protein expression.
Development Prospects of Small Nucleic Acid Drugs
With the announcement of the 2024 Nobel Prize in Physiology or Medicine on October 7, 2024, Dr. Victor Ambros and Dr. Gary Ruvkun were jointly awarded for the discovery of microRNAs and their role in post-transcriptional gene regulation. This has once again brought RNA-related research to the forefront of the industry.
The development of small nucleic acid drugs involves several processes, including selection of indications, target screening, sequence design, chemical modification, drug delivery, and process scale-up. For rare diseases, especially single-gene mutation rare diseases, the pathogenic mechanisms are clear, making small nucleic acid drugs highly adaptable. With ongoing advancements in core technologies such as small nucleic acid synthesis, modification, delivery, and scale-up, as well as verification of safety and delivery efficiency on technological platforms, siRNA has already explored lipid-lowering therapies for chronic diseases and is expanding to more indications.
Tsingke – Small Nucleic Acid Synthesis Services
Zixi Biotech, as part of Tsingke’s bio-manufacturing CXO business in the small nucleic acid drug solutions sector, has accumulated extensive project experience. Its services cover sequence design, synthesis, screening, and validation. Zixi Biotech has established large-scale oligonucleotide active pharmaceutical ingredient (API) production lines and offers oligonucleotide synthesis services from microgram (μg) to kilogram (kg) scales. The company supports deliveries from research-grade to GMP-grade, meeting customer needs for preclinical research. With experience in pilot-scale and scale-up processes, Zixi Biotech offers customized services and advice for clinical and commercial demands.
