Apr.23.2023
In the last two years, after small molecules and antibody drugs, small nucleic acid drugs have also gained attention.
Small nucleic acid drugs are a new class of drugs, consisting of nucleotides that act mainly on cytoplasmic mRNAs, recognising and inhibiting target mRNAs through base complementation to achieve regulation of protein expression for the purpose of treating diseases.
After decades of basic research, a total of 15 small nucleic acid drugs have been approved for marketing so far, including two main classes, small interfering nucleic acids (siRNA) and antisense nucleic acids (ASO).
Small nucleic acid drugs are important because they can overcome some of the limitations of traditional drugs or antibodies, such as targeting refractory molecules, specificity, stability and delivery. However, they also face a number of challenges such as toxicity, immunogenicity and high cost. Therefore, we are preparing a series of articles to present information about small nucleic acid drugs to the readers of BoP.
Before introducing the small nucleic acid drugs, we would like to compare the similarities and differences in order to avoid confusion.
Small nucleic acid drugs, small molecule nucleoside analogues and mRNA vaccines are all nucleotide-based drugs or vaccines, but they have different mechanisms of action and applications.
Small nucleic acid drugs are oligonucleotide sequences less than 30nt in length and include small interfering nucleic acids (siRNA), messenger RNA (mRNA), micro RNA (miRNA), antisense nucleic acids (ASO) and nucleic acid adaptors (Aptamer). These drugs achieve a therapeutic effect by binding to the RNA of the target molecule and inhibiting its translation or regulation. Small nucleic acid drugs are highly targeted and specific and can precisely regulate gene expression, and therefore have promising applications in fields such as gene therapy and gene editing.
Small nucleoside analogues, however, are a class of small molecular weight nucleotide analogues that are commonly used to treat viral infections and diseases such as cancer. These drugs achieve therapeutic effects by binding to the DNA or RNA of viruses or cancer cells and inhibiting their replication and transcription.
The mRNA vaccine is a new type of vaccine that stimulates the body's immune response by injecting the body with mRNA encoding the antigenic protein of the pathogen. The recent news of the approval of SYS6006, the first domestic new crown mRNA vaccine, for emergency use has brought renewed attention to mRNA technology, a method of using mechanisms within human cells to deliver specific genetic information to induce the production of a desired protein or antigen. However, mRNA vaccines need to be stored and transported at low temperatures, increasing the difficulty and cost of preserving and transporting vaccines.
Table 1: Small nucleic acid drugs, small molecule nucleoside analogues and mRNA vaccines are similar and different
|
Category |
Definition | Mechanism of action | Area of application | Representative drug or vaccine |
| Small nucleic acid drugs | Oligonucleotide sequences less than 30nt in length | Binding to RNA of target molecules Inhibits translation or regulation | Gene therapy, gene editing, etc. | Fomivirsen、Spinraza、Patisiran, etc. |
| Small molecule nucleoside analogs | Nucleotides with small molecular weights | Bind to DNA or RNA of viruses or cancer cells to inhibit their replication and transcription | Viral infections and cancers etc. | Riduxivir, acyclovir, ribavirin, oseltamivir, etc. |
| mRNA vaccines | Vaccines that encode antigenic proteins of pathogens by injection of mRNA produced in the body | Induces cells to produce the required protein or antigen to stimulate the body's immune response | Prevention of infectious diseases such as Newcastle pneumonia | Pfizer-BioNTech、Modern a、SYS6006, etc. |
The development of small nucleic acid drugs dates back to the 1970s when scientists discovered the mechanism of action of antisense oligonucleotides (ASO), oligonucleotides that inhibit protein expression by targeting the mRNA sequences of specific genes.
In the 1990s, RNA interference (RNAi) technology was discovered, whereby RNAi oligonucleotides can inhibit gene expression by interfering with the degradation and translation of mRNA. This technology has provided new ideas for the development of new gene therapy approaches.
In addition, aptamer oligonucleotides were also discovered during this period and proved to be highly specific drug targets with high therapeutic potential.
With the continuous development of gene sequencing and synthesis technologies, the design and preparation of oligonucleotide drugs has become increasingly precise and efficient.
In recent years, the development of oligonucleotide drugs has entered a new phase with the advent of mRNA vaccines. mRNA vaccines exploit the excellent properties of oligonucleotides to induce an immune response by delivering mRNA molecules encoding antigens, and have become an important tool in tackling infectious diseases such as COVID-19.
The following diagram summarises the evolution of chemical modifications of antisense oligonucleotides for therapeutic use.
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Figure 1: The ups and downs of small nucleic acid drugs.
Image credit: Reference 1
In the 1990s, various modifications of ODNs and ORNs were investigated and, based on RNase H activity, PS-ODNs became the first generation of antisense agents of choice. However, it was soon discovered that PS-ODNs had off-target activities, such as complement activation and sequence-specific immune activation, leading to questions about their mechanism of action and safety, and clinical development of most PS-ODN ASOs was halted.
Subsequently, parallel use of ORN modifications was performed for splice correction in cells. gapmer antisense designs, based on early work in the early nineties, provided key properties that became the second generation of antisense reagents of choice. Research into antisense chemical modifications has facilitated the development of other therapeutic oligonucleotides. Key modifications have been identified, such as PS-PDN and PS-ORN, 2'-modified or 2'-O-substituted ribonucleosides, bridging ribonucleosides and PMO, which are used in various nucleic acid therapies.
In recent years, gapmer ONs (e.g. mipomersen, inotersen, volanesorsen), 2'-MOE PS-ORNs (e.g. nusinersen), PMOs (e.g. eteplirsen, golodirsen, vitolarsen) and siRNAs (e.g. patisiran, givosiran) have been approved.
In recent years, with the advancement of research and technology, small nucleic acid drugs have seen rapid development and the number of nucleic acid drugs marketed worldwide is increasing year by year. 15 small nucleic acid drugs are currently approved worldwide, mainly for the treatment of hereditary and rare diseases such as Duchenne muscular dystrophy, spinal muscular dystrophy and hereditary transthyretin amyloidosis.
The classification of technical routes includes antisense nucleic acid (ASO), RNA interference (RNAi), CRISPR/Cas9, etc.
Among them, ASO, an antisense nucleic acid, precisely complements the target mRNA and degrades the mRNA, thus blocking its translation. There are currently eight ASO drugs approved for marketing worldwide and more than 50 ASO drugs in clinical research stage. Five of the approved ASO drugs are developed by Ionis, two by Sarepta and one by Shinyaku in Japan.
In addition to European and American pharmaceutical companies, the nucleic acid pharmaceutical industry in China is also growing. It mainly includes antisense nucleic acids, small interfering nucleic acids, nucleic acid aptamers, small activated nucleic acids, micro nucleic acids, mRNA drugs, nucleases, etc. Domestic pharmaceutical companies have also made certain achievements in research and development. For example, Suzhou Ribo Bio obtained the transfer of Chinese interest in a Phase II product, GCGR antisense nucleic acid, for the treatment of diabetes.
In addition, Japanese pharmaceutical companies and biopreneurs are developing nucleic acid drugs with their own technologies, such as Viltolarsen (Nippon Shinyaku), DS-5141 (Orphan Disease Treatment Institute) and STNM01 (TME Therapeutics).
The biggest challenge in the development and design of small nucleic acid drugs is how to solve the drug delivery problem or chemically modify the druggability of nucleic acid drugs, which has long been a weakness in the stability of small nucleic acid drugs. Innovative drug development for small nucleic acid drugs requires not only the patenting of nucleic acid sequences, but also the layout of various drug delivery systems.
As drugs that target RNA and regulate gene expression or function, small nucleic acid drugs have three main characteristics: high specificity, durability and curability.
Currently small nucleic acid drugs have shown promise in treating a variety of diseases, particularly hereditary and rare diseases. Many more drug candidates are in development for the treatment of common diseases such as cancer, cardiovascular disease and viral infections.
Of course small nucleic acid drugs face challenges in drug delivery in terms of stability, biodistribution, cellular uptake, endosomal escape and immunogenicity. New drug development teams have now developed various strategies to overcome these challenges, such as chemical modification, biocoupling and nanocarrier formulations.
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