Not only the door to the hope of MRNA technology to open the hope of the medical revolution

In the process of humans against the new crown epidemic, the advent of the MRNA vaccine was dazzling. my country is also vigorously developing its first MRNA new crown vaccine. Watson Biological recently announced that it has ended the clinical trial stage and is undergoing data statistical analysis.

However, the use of mRNA technology is far more than just making infectious diseases. It solves the problem of manufacturing of protein drugs, which not only allows us to cure cancer and healing autoimmune diseases, but also greatly reduce the price of treatment, so that more people can afford MRNA therapy.

In mid -July this year, my country's first nucleic acid industrial park was broken in Shanghai. In the future, various vaccines and drugs based on MRNA technology will be the development direction of the biomedical industry.

Compilation | Wang Wang

Revelation from the virus

For humans, the virus has always played the role of the enemy at many levels, but learning from the enemy is a thing that humans are very good at, as well as the enemy of the virus.

When the virus invades the human body, it can hold human cells to work for it, produce genetic materials and coats it needs, and then produce more viruses. This trick is insidious and works. As an invaders of the cells, they can use human cells to quickly accumulate their own strength, and then launch an attack on the immune system.

After clarifying this, scientists start thinking that if the virus can turn our cells into its protein processing factory, why can't humans use the same strategy to make protein?

It turns out that we can. After this visionary idea was proposed, after decades of research, scientists finally successfully turned the imagination into reality when the new crown epidemic came in -PFIZER/BIONTECH vaccine (Pfizer vaccine) and other new new crown vaccines were imitated. The characteristic of the virus: They use MRNA (MESSAGE RNA, Credit RNA) to instruct our cells to produce protein fragments that can be recognized by the immune system, so that the immune system can learn the invaders and generate immunity.

The rapid development of this technology has benefited from the popularity of the new crown epidemic: the epidemic has spread rapidly, causing an urgent demand for vaccines, and promoting the development and development of new vaccines to accelerate and accelerate. People have witnessed the potential advantages of MRNA vaccine rapidly and low cost. Pieter Cullis, a professor of biology at the University of British Columbia, Canada, described: "The rapid development of the new crown vaccine has revealed to what extent the speed of human development of new drugs can reach. It took three months. "[1]

The new crown vaccine is just the beginning. If we can use this way to recruit our body -just like a recruitment -actively launched a counterattack against the disease, then it is as small as bacterial infection, as large as autoimmune diseases, or even difficulty in overcoming it. Genetic diseases and cancer can't escape the counterattack of this weapon. Cullis described "this is a drug revolution, and its development speed and detection speed are very fast." Although we have just stood at the starting point, a breakthrough like the MRNA vaccine has just appeared, but it is no exaggeration to say that MRNA technology will definitely change the situation of human and disease resistance.

Since modern times, medicine has been improving, but there are few progress that can be called "breakthrough". The MRNA vaccine can be regarded as one of them. Why are scientists so excited about the potential of MRNA technology and related therapies? This needs to start with the history of the vaccine.

From living virus to instructions

Early vaccines are generally composed of "living" viruses. These viruses usually have mutations that weaken them to toxicity, making their risk lower than wild viruses, and at the same time, they can cause immune reactions. Living vaccines are very effective, once to allow humans to avoid large -scale disasters, such as we know early Tianhua vaccines and rabies vaccines.

However, there are disadvantages of live vaccine: First, manufacturing is very difficult, because the virus can only be produced by live cells; second, the complete virus of the poisoning version is still threatening, which may hurt those who have weak immunity; the most important thing is that the most important thing is The virus used to make live vaccines is possible, which makes them double the risk, just like the virus reduction vaccine oral oral oral oral oral oral oral oral oral oral oral oral oral oral body may occur in the body. Later, it will lead to the spread of the virus and cause serious consequences (see "Save Ten Thousand People, but not to be seen by his peers: only to promote new technologies can it be considered a good science?

Therefore, with the advancement of science, many modern vaccines have abandoned the "live virus" used in the early days and began to use analog virus to produce vaccines. At present, many sub -unit vaccines do not even need to use complete viruses (regardless of life), and only need to use virus fragments that can be recognized by the immune system, such as protein or polysaccharides, can play an immune role. However, it is still very difficult to produce such vaccines because any protein -based drugs are limited to one point: they must be produced in live cells. Traditional vaccine development has been bound by this point. From the amount of initial testing preparation to large -scale production in the later stage, production capacity needs to be solved at each stage. If the candidate vaccine is not effective, it is difficult to adjust its production route.

However, just decades ago, biologists borrowed the reproductive model of the virus and realized a potential shortcut: instead of injecting part of the protein in the body in the body, it is better to provide our body with a genetic recipe for making virus protein. Let the body make these antigens by themselves. Our body is a natural protein processing factory, but it usually only produces the protein required by the human body according to a specific template. These protein formulas are generally stored in our nuclear DNA forever. When cells need to make protein, the RNA copy will be created in the form of mRNA. These mRNAs pass the instructions to the protein manufacturing factory of the cell -ribosome. This process will last for several hours or days until the mRNA breaks down and the protein production stops. MRNA technology development

In 1990, biologists used mice experiments to prove that adding protein DNA or mRNA to live cells can allow mice to produce a large amount of this protein. This discovery is jumping because it is much easier to produce DNA and RNA in the laboratory compared to the production of protein [2]. This experiment proves the feasibility of the "shortcut" for us: if we can accurately analyze the mRNA sequence corresponding to the protein that causes immune response, then we can create prototype vaccines at a very fast speed. And in the process of manufacturing this vaccine, it does not need to rely on any biological process, so the production speed will be greatly improved than that of traditional vaccines.

But there is always a distance between theory and practice. How to figure out the principle, how do you implement this "shortcut"? The first obstacle encountered by scientists was the human body's defense measures for exogenous RNA. Because many viruses and parasites use RNA to hold cells and produce the nutrients required for their reproduction, the human body cannot respond without response -in our blood, sweat, and tears "Material, this enzyme can quickly break down any RNA found outside the cell. Even if the external RNA breaks through this line of defense and successfully invades cells, they will still trigger a series of defensive reactions from cells. Anna Blakney, a biological engineering expert at the University of British Columbia, described it: "In continuous evolution, human body has learned to use various means to detect and defense RNA virus." [1]

Maybe someone will ask, does the vaccine need to cause the human body's immune response? Indeed, the vaccine requires the alarm clock of the immune system to take measures to take the virus. But if the human body's response to the introduction of the RNA is so strong that they have time to express the protein that they need to express, then the immune response to the virus we want to get will not be able to talk about it. Therefore, most biologists have had a negative attitude towards MRNA vaccine technology before, and more researchers have focused their attention on DNA -based vaccines. But so far, the DNA vaccine tests are disappointing, and no vaccine can cause a strong immune response.

MRNA's late -time high songs benefited from two key breakthroughs. The first appeared in 2005. Katalin Karikó and Drew Weissman successfully modified the MRNA to allow it to avoid immune detection in cells. Due to the great decrease in the number of mRNA damaged by the cell defense mechanism, protein output increased by nearly 1,000 times [3]. (For details, see "Middle -aged unemployment, cancer, she saved the whole mankind with a forty years of counterattack, and also trained an Olympic champion")

The second is the breakthrough of packaging technology. The researchers successfully packaged MRNA in lipid nanoparticles to protect them from the decomposition of RNA enzymes in the blood and deliver them into the cells [4]. This method must overcome a huge challenge: RNA with negative charge, so it will only be combined with the lipid with positive charge, but the lipids with positive charge are toxic, and they tend to tear the cells. Scientists cleverly resolved this problem: they developed a lipid with initial charge, which can successfully pack RNA. After this lipid enters the body, it will lose positive charge and lose toxicity. After years of gradual improvement, until the 2010, a key technology called Patisiran's drug proved that this technology was safe to the human body in human trials and paved the rapid research and development and use of the MRNA vaccine. Road [5].

After these two key breakthroughs appeared, the prospects of MRNA technology began to become clear and happy. In March 2013, H7N9 bird flu broke out in China, with about 100 people infected. After the virus's gene sequence was released online, a team of Novarty Pharmaceutical developed a MRNA candidate vaccine from scratch in just eight days. Within a few weeks, the candidate vaccine was proven to have a good effect on mice [6]. Compared with the one -year or longer R & D time of traditional vaccines, the R & D speed of the MRNA vaccine has created an amazing historical record. But because the H7N9 epidemic ended quickly, the work did not continue. Since then, due to the unknown prospects and profits of new technologies, large pharmaceutical companies have given up and continue to follow up, leaving the opportunity to smaller companies such as Biontech and Moderna.

Before the global new crown virus was popular in 2020, many MRNA therapies were already in the test. These small tests are mainly used to treat cancer by inducing mutant proteins in tumors, but no therapy has been approved for humans. After the global outbreak of the new crown epidemic, the MRNA technology coincides with it, and the urgent demand for the market has greatly promoted its R & D speed. It did not live up to people's expectations -in August 2020, the vaccine BNT162B2 jointly developed by Pfizer and Biontech became the first MRNA vaccine to be fully approved by FDA. The feasibility of MRNA technology has been favored by many investors after being fully proven in the epidemic. Cullis said: "This is like a gold rush hot ... MRNA technology obviously has broad application prospects. You can express any protein you want."

Low price is the king

In recent years, with the development of technology, the pharmaceutical pattern has changed. Some protein -based large -molecular drugs have been approved to be listed. They are more targeted than traditional small molecular drugs and better treatment effects. Most of these macromolecular drugs are precisely designed to fight against specific diseases. Antibodies are a special type of protein macromolecular. It is a type of protein produced by the human immune system for invaders (such as antigens) that causes diseases (such as antigens). The antibodies designed and processed by scientists can be used for multiple purposes: in addition to the commonly mentioned treatment of cancer, they can also help the treatment of autoimmune diseases, a series of infectious diseases, and even difficult migraine.

These carefully designed drugs generally have good curative effects, but they also have obvious disadvantages: their production is difficult and time -consuming, so the cost is incredible. For some patients who need to inject antibodies for a long time, this will be a huge sum of money. For example, a fatal kidney disease AHUS (ATYPICAL HEMOLYTIC UREMIC SYNDROME) can be treated with an antibody drug called Eculizumab, but it is one of the most expensive drugs in the world. Patients need to spend about 300,000 pounds per year (about 243 (about 243. 10,000 yuan) text [7].

Why is it so expensive? If we know how difficult it is to make protein in the factory, we may understand. We know that the function of protein not only depends on the accurate arrangement of amino acids, but also depends on the three -dimensional structure formed by their folding, and each step of this folding can only occur in living cells. This means that this three -dimensional structure needs to be accurately generated in the manufacturing process. In the subsequent purification, storage, and transportation, this structure is not damaged, and all these steps must be targeted at each different protein. Customized.

In contrast, making MRNA is much simpler, because the most important information they encoded -alkali -based sequence -can be manufactured by chemical technology, no living cells are required, and different mRNAs can be manufactured using the same production process. If we can use MRNA technology to transfer the steps of drug manufacturing to our bodies, that is, let our body actively produce the protein required for production according to the MRNA instructions (as MRNA vaccine) The cost will be greatly compressed. Compared with protein drugs, this is a huge advantage, and new therapies will also appear faster and more likely. Ideally, we can use MRNA drugs to treat any disease.

However, in actual operation, there are still differences between MRNA drugs and mRNA vaccines: the former allows the body to directly produce a large number of antibodies, and the latter is to induce the human body to produce antibodies by injecting the MRNA injected by the virus. The effect of vaccine only requires a small amount of virus protein, and because foreign protein can cause inflammation, the production of viral protein must be limited to a small part of the body. For example, the upper arm muscles are generally selected like vaccine injection. And if you want the human body to produce a large amount of antibodies, a large amount of mRNA needs to be injected into the blood. They are almost all absorbed by hepatocytes, which produces specific proteins (antibodies) and releases them into the blood. In essence, this process has turned the liver into a biological reactor for the production of various protein drugs [8].

This design was not verified until 2017. Norbert Pardi, a professor of microbiology at the University of Pennsylvania, proves on mice that this idea may be true [9]. This also means that such mRNA therapies are still in the early stages. Among many companies that actively develop MRNA therapy, Moderna has gone forward. In 2019, the company reported the first report of the MRNA positive experiment that can directly encode antibodies in the human body. The antibody is performed directly [10].

It is foreseeable that MRNA technology can be used not only for producing antibodies, but also various other proteins. In August 2021, Moderna began experimenting with a new MRNA. The mRNA could encode two signal proteins at the same time, one for treating autoimmune diseases, and the other by replacing the defective enzymes to treat genetic diseases by replacing the defective enzymes to treat genetic diseases Essence If this type of test is successful, the treatment method based on MRNA technology may occur. This will bring a great gospel to patients -not only the price of drugs will become low (compared to protein drugs), the dose required will also be less than the dose of directly injection protein. In addition, a single -dose MRNA can continue to produce protein for several days, and we can manually modify the mRNA to make it more effective. Compared with direct injection antibodies, there is a slight delay in producing antibodies with MRNA. Some scientists have had doubts about the lag of mRNA therapy, but research has found that these tiny lag may be unrelated, and even if they need urgent treatment such as poisoning such as poisoning. For example, a recent study on the experimental mouse found that in the face of the fatal dose of botulinum toxin, the injection mRNA is as effective as the direct injection antibody [11].

Future

As the problems are solved one by one, MRNA therapy has stepped into reality step by step. At present, it is urgent to solve the targeted problem -if we can try to deliver the drug to a specific organ or tissue, such as the brain or bone marrow, then MRNA technology Uses will be wider.

Although nowadays, the existing drug delivery level can be used and enough. For example, the AZD8601 of Moderna is already conducting human tests. Growth. However, many genetic diseases are caused by lack of functional proteins in some tissues. Unless it is injected directly to the tissue, it is difficult to deliver MRNA to other parts outside the liver.

In this regard, scientists have proposed several solutions. One of the strategies is to put the mRNA in the virus shell that is known as a specific cell type, and use the virus as the carrier to pass the mRNA to a specific tissue. However, the immune system is memoryful and attacks the virus that has appeared, so this method is used once, and it cannot be used again. In August 2021, a team reported that they successfully created a shell that could be used as a carrier based on a human protein, which was expected to solve this problem [12]. However, Blakney believes that "this is a feasible strategy, but there are many places that need to be improved and tested.

The use of MRNA technology to fight cancer is achieved by a law therapy called "Cancer Vaccine". The overall idea of ​​cancer vaccine is to allow a person's immune system to accurately distinguish tumor cells and normal cells. By importing tumor antigen in various forms (such as nucleic acids, protein polypeptides, etc.) into the patient So as to remove tumor cells. Due to different tumor cell mutations in patients with different cancer patients, cancer vaccine is generally personalized and customized. Gene sequencing for individual tumor cells needs to be identified to identify targets. This target is usually mutant protein in tumor cells. One of the advantages of using MRNA technology to customize cancer vaccines is that once these targets are determined, the cancer vaccine can be produced quickly and cheaply, and the price of vaccine may decline.

However, the difficulty of cancer vaccine is not technology, but to clarify the characteristics of tumor cells. Smita Nair, a Duke University in North Carolina, believes that it is not easy to find tumor -specific targets and make the body actively attack tumor cells because tumor cells are very cunning. The protein on the surface is very similar to the protein of normal cells, and it is difficult to detect the immune system. Vaccination for cancer is much more difficult than infectious diseases. This work is worth looking forward to, but it is very challenging.

According to statistics, there are currently six MRNA therapies in the world for cancer. Four of them are personalized vaccines. In 2021, a total of 71 MRNA vaccine tests were approved, and only two were in 2018. Although most experiments are still targeted at infectious diseases, people still have quite high expectations for MRNA therapy.

There is no doubt that the MRNA vaccine and related therapies have broad prospects, but we still need to maintain a cautious attitude. The experiments of the Chikunya Virus antibody are still the only experiments produced by the therapeutic protein in the human body so far. The complete results have not yet been announced, so we are not sure that this method is both safe and effective In, we still need to pay attention to the toxicity it may produce and conduct experiments related to toxic testing in the later stage.

At present, other related animal tests, especially the results of non -human spiritual long animal experiments, are positive, and show the amazing potential of mRNA therapy. Although the road ahead is full of challenges, if we can overcome the remaining difficulties, such as the targeted and storage problems mentioned earlier (the existing MRNA vaccine must be kept frozen), we can use this virus body from the virus body The strategy learned to treat almost all diseases.从某种意义上说，mRNA疫苗和疗法实际上并没有太多革命性的东西，因为最终发挥作用的都是蛋白质，只不过传统疗法是直接将这些蛋白质递送到人体内，而mRNA 疫苗则是Use the natural protein manufacturing factory of the human body to transport instructions to achieve the same results. However, if the cost and speed of R & D and production and testing, MRNA technology has thorough change and absolute advantages. In this new crown epidemic, less than a year after the MRNA vaccine was launched for the first time, hundreds of thousands of people had been saved. Therefore, we can not exaggerate the MRNA vaccine and various therapies that will follow it as the medical revolution. Its future and human future are still hopeful.

references

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source:

https://www.sciencedirect.com/science/article/pii/s0262407921018510

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