The Bottleneck of RNA Drug Delivery System (II)

 

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The Bottleneck of RNA Drug Delivery System (II)

A large number of mRNA preparation systems have been reported, and many of them have entered clinical trials. These preparation technologies all achieve the delivery of mRNA vaccines by forming special mRNA carriers. These carrier technologies include: protamine carrier technology, nanoparticle liposome carrier technology, multimer carrier technology, etc.

Protamine is a natural cationic protein that can complex negatively charged mRNA molecules into nano-scale nucleic acid particles, thereby protecting the mRNA from degradation by RNase in the serum; but because the combination of protamine and mRNA is too tight. Therefore, the protein expression efficiency of the mRNA vaccine using this preparation will be limited. In addition, the expression of antigen is also largely affected by the ratio of protamine and mRNA. The RNActive platform developed by the German CureVac company successfully solved this problem. Among the protamine-mRNA complexes obtained through the RNActive platform, protamine as a TLR7/8 antagonist can induce Th1 cell responses, and mRNA can express the target protein to induce specific immune response.

The principle of lipid nanoparticles (LNPs) carrier delivery of RNA is not fully understood, but it is generally believed that LNP is bound to the cell membrane through non-covalent affinity and is taken up by endocytosis, and the mRNA escapes from endocytosis after entering the cell. The vesicles are released into the cytoplasm to express the target protein. LNP can also be expelled from the cell through the opposite exocytosis, which is also a point to be noted when administering mRNA through LNP.

The multi-carrier technology is not widely used in clinical applications than liposome carriers, but it also exhibits excellent properties as a carrier for nucleic acid drugs. When designing a multimeric carrier, additional consideration needs to be given to the molecular weight and the amount of charge of the multimeric carrier. Excessive carrier molecules and excessive charge capacity usually lead to too stable binding of the carrier and mRNA molecules, resulting in mRNA expression. The efficiency is too low.

It can be seen that the delivery technology platform is one of the keys to mRNA drugs. At present, mRNA still needs to be delivered by nano preparations, so it is still difficult to target tissues other than liver and spleen. At the same time, the low membrane permeability of mRNA drugs also leads to wide individual differences. If the membrane permeability of the drug is 1%, then 1% Individual differences will result in twice the effective drug concentration difference, but if the membrane permeability is 50%, then the 1% individual difference is irrelevant. The industry's strategy now is to first select projects with a larger safety window, such as vaccines, but if they expand to more complex targets, the industry needs to find biomarkers that can monitor drug response.

Small nucleic acid drugs are maturing, delivery is still the bottleneck

At present, the narrow sense of small nucleic acid refers to short double-stranded RNA fragments (siRNA) that mediate RNAi, mainly covering siRNA, miRNA and antisense nucleic acid. Because of the better efficacy of siRNA drugs and the breakthrough in technology, it has become the most concerned type of technology.

Among them, antisense nucleic acids are the earliest found, the most approved drugs are more mature, but antisense nucleic acid drugs are not as efficient as siRNA drugs. siRNA drugs still have a certain bottleneck in the delivery of tissue cells. The first siRNA drugs listed in 2018 have already effectively delivered to organs and tissues. With the further breakthrough of drug delivery system, siRNA drugs will gradually replace antisense nucleic acid drugs and become mainstream RNAi drugs.

The miRNA and siRNA have a completely different mechanism of action through 21 nucleotide pairs, and only need 2-8 nucleotide pairs to work. Therefore, miRNA usually acts on one face rather than one point, and acts on a coordinated network rather than a single channel. Related technologies need to be further broken through.

From 2005 to 2009, the RNAi field attracted billions of dollars of capital investment, spawning many small biotechnologies company, but the industry has encountered bottlenecks. In 2006, Merck acquired Sirna, a company specializing in the development of RNAi drugs, for US$1.1 billion; in 2007, Roche and Alnylam Pharmaceuticals signed an agreement worth up to US$1 billion to acquire the company's RNAi technology. However, the effect of RNAi drug treatment is far less than expected. The poor systemic drug delivery effect and the serious side effects caused by off-target have become the biggest obstacles. The serious side effects of drugs have never been overcome, and research and development have fallen into a dilemma. Although the first round of capital entry did not achieve the expected return, it has promoted the development of the industry to a certain extent, causing companies such as Alnylam, Quark and Arrowhead to grow up.

The research and development in the field of small nucleic acid drugs has the following directions. On the one hand, the development of gene sequencing technology and the reduction of sequencing costs have provided the possibility for the industrialization of small nucleic acid drugs; on the other hand, RNA modification technology has increased the stability of RNA in the blood. Drug delivery system breakthroughs make drugs more efficient and safe.

From 2013 to 2016, successive antisense nucleic acid drugs were approved for marketing. In 2014, Sanofi acquired a 12% stake in Alnylam for $700 million, but research and development were also difficult; Arrowhead's functional cure for hepatitis B RNAi drug ARC-520 stopped phase II research and development due to animal deaths in animal experiments; In 2016, Alnylam's RNAi drug Revusiran failed in the phase III clinical phase, killing 18 patients, causing its stock price to be cut at the time and suffered a serious setback.

To be continued in Part III…

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