The Bottleneck of RNA Drug Delivery System (III)

  • Until the end of 2016, the breakthrough of technology and the approval of new products set off a new round of investment cooperation. Bios/Ionis' antisense oligonucleotide Nusinersen for the treatment of spinal muscular atrophy (SMA) was approved by the FDA for marketing and achieved sales of US$882 million in 2017. The industry generally gives estimates of sales peaking at US$2 billion. In 2017, Patisiran's clinical phase III results exceeded expectations, marking a major breakthrough in nucleic acid interference drugs and regaining confidence in the industry. In 2018, Ionis and Alnylam's two orphan drugs for the treatment of polyneuropathy caused by hATTR were successively approved. Among them, Patisiran became the world's first approved siRNA class of small nucleic acid drugs, which has a huge exciting effect on the entire field. At the same time, capitals have returned to the RNAi field, setting off a second investment boom.

    The indications of small nucleic acid drugs cover a wide range, including tumors, rare diseases (amyotrophic lateral sclerosis, Duchenne muscular dystrophy, spinal muscular atrophy), viral diseases, kidney diseases, cardiovascular diseases (insufficient blood coagulation, Dyslipidemia, etc.), inflammatory diseases (asthma, arthritis, colitis), metabolic diseases (diabetes, non-alcoholic steatohepatitis), etc., the potential market scale is very broad.

    Among them, rare diseases and tumors are the most widely used fields of small nucleic acid drugs. So far, 9 small nucleic acid drugs have been approved for marketing, of which 5 drugs are orphan drugs, and also the first drug in the field of the disease, to a certain extent meet the needs of rare patients who have not previously had treatment.

    A report issued by the life science business information agency EvaluatePharma (EP) on World Rare Disease Day (EvaluatePharma Orphan Drug2017Report) shows that total sales of rare disease drugs in 2016 were US$114 billion, accounting for 16.4% of the global non-generic drug market. By 2022, this number will rise to 209 billion US dollars, and sales of rare diseases will account for 21.4% of the entire market. RNAi technology can work against known rare disease genes, overcome the shortcomings of certain target proteins that are difficult to make medicine, and make breakthroughs quickly. The report predicts that by 2025, the market for small nucleic acid drugs will exceed US$10 billion.

    The development of hot small-accounting drugs is not without its shortcomings. For example, in 2009, Bevasiranib, the first drug to conduct clinical trials of siRNA, was discontinued in phase III clinical trials because of poor results. Poor targeting, off-target effects and stability issues are the most important factors affecting the efficacy of siRNA drugs.

    1) Poor targeting: siRNA is a negatively charged biologically active macromolecule, it does not have the ability to target tissues or cells, and its ability to penetrate cell membranes is extremely poor.

    2) The off-target effect is serious: In addition to the antisense strand of the siRNA molecule can mediate the expression and silencing of homologous genes, the antisense strand can cause the suppression of some non-homologous genes through the miRNA pathway, and the sense strand mediates the expression of its homologous genes silence and causes off-target effects mediated by the sense strand; at the same time, unmodified double-stranded RNA also causes activation of some innate immune mechanisms. In small nucleic acid pharmaceutics, these will produce toxic and side effects of drugs, which seriously affect the application of RNAi technology.

    3) Poor stability: RNA is easily degraded by blood nucleases in the human circulatory system, and its stability is poor.

    Therefore, similar to mRNA, delivery platform development is the focus of the entire chain. At present, in order to solve this problem, research and development of drug delivery system technologies are in full swing, focusing on lipid nanoparticles (LNP) and GalNAc (N-acetylation Galactosamine) coupling technology development and application.

    RNA aptamers is temporarily on the edge of the industry

    In August 1990, scientists from the University of Colorado and Massachusetts General Hospital (L. Gold and J. Szostak) published articles in Science and Nature, respectively, showing that through in vitro evolution and screening, RNA molecules that are tightly bound to the target molecule can be obtained. Affinity and specificity are comparable to monoclonal antibodies. They called this screening process "Systematic Evolution of Ligands by Exponential Enrichment (SELEX)". The name Aptamer comes from the Latin word "aptus", which means "to fix".

    This breakthrough research by Gold and Szostak confirmed that nucleic acid molecules can form binding pockets and clefts that interact with molecular targets through intermolecular forces such as hydrogen bonding, van der Waals force, and hydrophobic interaction with three-dimensional structure, high affinity and specificity to recognize and bind target molecules.

    SELEX conforms to the evolutionary principle of survival of the fittest. After incubating the RNA library with the target for a certain period of time, unbound molecules are removed, and the bound molecules are eluted to form a new compound library by RT-PCR. Repeat the above process. After 8-20 rounds of screening, aptamers with high specificity and high affinity can generally be obtained. At present, there are more than 1,000 aptamers reported for academic purposes in treatment and diagnosis.

    Nucleic acid aptamers and antibodies are often compared in the industry because they have many similarities. Both have affinity and specificity, and both can specifically bind to targeted targets, and thus the characteristics are applied in the field of biomedicine. However, with the development of screening technology research, more and more target molecules have obtained high-affinity, high-specificity aptamers, and have broad application prospects, especially in the field of molecular recognition inspection. However, compared with mature antibody experiments, aptamers can supplement the lack of antibody performance, but cannot completely replace antibodies.

    Although nucleic acid aptamers have been developed for nearly 30 years, there are still many problems that hinder their practical application. For example, the performance in the body is very poor, and it is easily degraded in the blood; the nucleic acid molecular structure is too small, the kidney clears quickly, and the pharmacokinetic performance is poor when used as a drug; the nucleic acid aptamer as a nucleic acid molecular probe has very limited chemical force and increases when it is difficult to bind target molecules, the screening is difficult and the sensitivity is not high enough; when using aptamers to find targets, there is a lack of high-throughput screening and identification methods; for immunohistochemical applications, the specific aptamers available are few, the clinical application is not recognized, and it is urgent to be promoted. The application of aptamers is on the edge of the industry.


    The RNA world hides many molecules with therapeutic potential. However, in addition to obstacles in the design stage of RNA drugs, such as immunogenicity, the core problems, such as delivery, off-target side effects, and general toxicity, are difficult to avoid in subsequent clinical trials. At present, despite the continuous development of delivery systems represented by nano-scale non-viral particles, problems such as low efficiency and lack of targeting mechanisms have not yet achieved breakthrough progress.