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In the decades since Genentech’s birth, the biomedical industry has seen countless new technologies, countless new companies. Many of these technologies have been touted as a revolutionary new breakthrough in recombinant DNA, such as gene sequencing, gene editing and RNA interference. But today, no single technology can revolutionize the pharmaceutical industry.

Moderna Therapeutics’ mRNA treatment is also a new technology that promises to change the world. But the company has been secretive until recently, when there was little understanding of Moderna. Moderna has raised more than $2 billion, valued at $7.5 billion, but the question is whether the company’s product line will support such a high valuation. Can mRNA therapy become the next breakthrough in the pharmaceutical industry? This article will uncover the biggest unicorn in the biotech field.

The mRNA’s adventure

Derrick Rossi did not like Paris, in Paris one and a half years he often go to parties, and night song, barely had a full night’s sleep, such a life is not about he wanted.

Rossi went to Paris to study after finishing his undergraduate and master’s degree at the university of Toronto in Canada, but after spending more than a year in Paris, he began to realize that it didn’t seem to be the right decision. Rossi stayed in Texas for a while after leaving Paris before going to the university of Helsinki in Finland.

Perhaps to outsiders such schooling experiences is some, but Rossi does not think so, this kind of complex background allows him to contact multiple research areas, also for the future of the road of independent research laid a very solid foundation.

But until Rossi graduated, he had not done research in stem cell research, and only occasionally read the literature and felt that the age of stem cells seemed to have arrived. And as research goes deeper, anti-aging is no longer considered a pseudoscience.

Rossi had a hunch, it seems that stem cells will there is a strong correlation between and aging, so, after graduating from the Dr Rossi went to Stanford university to study in the field of stem cell and aging.

Rossi loves Boston, and often rides his bike around the city. In 2007, six months after Rossi became an assistant professor at harvard medical school, he finally got his own lab. Rossi’s main research direction was hematopoietic stem cells, but after he had his own lab, he began to want to do some other, more interesting research.

The reason for this is that Rossi had read a research paper published in the Japanese scientist yamanaka that was enough to shock the world. Probably a lot of people are already familiar with the work that yamanaka did at the time. Yamanaka is one of the leading cofounders of induced pluripotent stem cell technology.

Until the induction of pluripotent stem cells, stem cell research had been very dependent on embryonic stem cells. And embryonic stem cells are derived from discarded embryos, so there are numerous ethical issues in these studies.

But yamanaka’s induced pluripotent stem cell technology perfectly avoids the problem. Initially the mountains stretch “team found that through the slow virus vector Oct4 and Sox2, c – Myc, Klf4 the transcription factor gene into four adult cells, can convert adult cells into pluripotent stem cells similar to embryonic stem cells (iPS cells). This is a landmark study, and yamanaka won the Nobel Prize in 2012.

But Rossi believes that while iPS technology is extremely important for basic research, it still has many drawbacks if iPS technology is applied to the field of disease treatment. Instead of using DNA viruses as a gene carrier to induce normal cell transformation, the DNA virus could actually induce unexpected mutations in the cell genome.

Although lentiviruses are safer than some types of retroviruses, Rossi’s fears are not entirely unreasonable. This is one of the main reasons for the near-destruction of gene therapy, which can be referred to the author’s previous article on gene therapy. Gene therapy can lead to deadly side effects, or induce leukemia, if certain types of viruses are selected as carriers.

So Rossi thinks that if you optimize the technology of yamanaka, you don’t use viral vectors to import genes, and you might be able to avoid these problems. Rossi’s solution sounds very simple: mRNA is used as a genetic material to express these transcription factors. Unlike DNA viruses, mRNA does not integrate into the genome of the target cell, so there is no risk of developing cancer.

A year and a half later, after the Rossi lab’s blog, Luigi Warren finished the experiment. Rossi believes that the findings will cause a big shock in the academic field, but he is not willing to finish only published academic articles will end this topic, but hope to be able to commercialise the results of this research on at the same time.

But as a junior, an assistant professor at harvard, he did not enough social resources to support him to finish this matter, and he has no prior experience, Rossi is really don’t know the so-called commercial how to work. So he found his colleague, Tim Springer, hoping to get some tips from Springer.

Springer has had some experience with academic achievements, and he thinks that Rossi’s research is truly remarkable. So Springer decided to introduce a person to Rossi: Robert Langer.

This is probably the most coveted countless young scientists things, because the Boston has been doing the rounds in a word, if you want to create a biotechnology company, you must first meet Robert Langer.

The birth of the Moderna

Langer is a successful scientist who has published more than 1,000 academic papers and applied over 800 patents. Langer’s email inbox is filled with emails from young scientists around the world. This is actually because Langer has founded more than 20 companies, from anti-tumor drug delivery systems to hair styling hairspray, which can be said to be all-around. These young scientists hope to get some guidance and advice from Langer.

Langer’s daily schedule is so full that he is so busy that he can reply to seven emails on his cell phone from the bathroom. So most people can make an appointment to Langer for a very short period of time, about a dozen minutes, to more than half an hour. But Langer gave Shi PuLin Ge and Rossi two hours.

One day in late May 2010, the weather was unusually warm. Rossi and Shi PuLin Ge went through the MIT campus to Langer’s office to meet him. The trio sat around Langer’s desk, and Rossi took out his laptop and began to explain the experimental data to Langer.

While using mRNA expression inside the cells to produce proteins that sounds simple enough, but in practice there are many obstacles, such as cell after perception mRNA invasion will activate the body’s natural immune system degradation of these foreign nucleic acid. It is also a good self-protection mechanism for the body to prevent cells from being manipulated by intruders.

Rossi, however, breaks the cell’s own defense mechanism by modifying the mRNA’s nucleotides to avoid the innate immune system. When mRNA that can express specific transcription factors goes into the cell and translates it into the corresponding protein, the adult cells can be transformed into iPS cells successfully.

Rossi will think this way to induce cell transformation is a very great achievement, but Langer after listening to the iPS cells don’t interested, he thought it was interesting to the first part of the experiment, namely Rossi will mRNA delivery method to the inside of the cell.

And Langer is already imagining the potential of this mRNA modification technology, Langer said to Rossi, not just to iPS cells, you can apply this technology to any field.

Three days later, Rossi appeared in the offices of Flagship Ventures. Flagship is a very interesting company, because they not only invest in startups, but they also have startup incubators within the company, and they create new companies themselves.

Flagship’s CEO is Noubar Afeyan. In the 1980s, Afeyan received a doctorate in biochemistry from MIT. At that time, the biotechnology industry was barely a few years old, and the biotechnology industry was generally believed to have originated from Genentech in 1976.

When Afeyan was a graduate student, Genentech was a very young company. Although at that time, the industry scale is still small, but people have a great expectation on this field, hope for explosive growth, in the field can greatly improve the level of human health.

And in the decades since, there have been countless new technologies, gene sequencing, gene therapy, antisense therapy, RNA interference, stem cell therapy. Seeing him rise tall, see him banquet guest, see his building collapse. Over the decades, Afeyan has witnessed the ups and downs of these technologies, so he’s not a fanatic about new technology.

However, when Rossi found him and told him what he thought, Afeyan felt that Rossi’s mRNA technique was not simple. Afeyan, like Langer, also found that in Rossi’s experiments, mRNA was much more important than inducing iPS cells.

Afeyan has been deeply attracted to the mRNA technology after talking to Rossi. A variety of therapeutic proteins can be produced within the cell, which will be a new way of producing drugs.

MRNA translates as protein. Source: Science

That evening, as Afeyan was driving home on his way home, he was thinking about Rossi’s research, and he was excited about the prospect of mRNA technology. When he returned home, he was already convinced that Rossi’s technology would be a huge breakthrough for the industry. Afeyan feels that in his years of investing, this is the most promising technology he has seen in the field of disease treatment.

Two weeks later, Rossi saw another man, Ken Chien. Chien is a scientist at Harvard University who specializes in heart stem cell research. Chien and Rossi quickly teamed up for another experiment, and found that heart cells were able to quickly absorb the modified mRNA and translate it into protein.

Chien, meanwhile, began to get excited. He has been studying restoration of myocardial and vascular injury caused by myocardial infarction, but Rossi’s technology provides a plausible solution for him, so he also hoped to incoming, to join them, set up a new company.

So, with the support of FlagshipVentureLabs, Rossi, Langer, Afeyan, and Chien, together, formed Moderna. The idea for the company’s name comes from the acronym Rossi: Modified RNA. Tim Shi PuLin Ge became one of the company’s earliest investors and board members.

In 2010, Rossi applied for a patent for the use of modified mRNA to make stem cells, and published the article in September. At this point, the company still lacks a central figure, the CEO of the company.

In early 2011, Stephane Bancel was CEO of BioMerieux, a French diagnostic company. Afeyan has repeatedly tried to hire him to run some start-ups, but Bancel has always refused. The goal of Bancel is clear: he can really try to run a small company, and the business can be very risky. But one must be satisfied that if the company succeeds, it must be enough to change the world.

At the time, Moderna’s pie was big enough. One day in February 2011, Bancel accepted an invitation from Afeyan to meet with him. Afeyan bluntly told Bancel that he wanted Bancel to run a start-up, and that the company has so far had only a handful of people and only had one mouse experiment.

He told Bancel that while the company was small, Moderna would be able to produce a candidate drug in just a few weeks if the mRNA technology was successful.

In addition, from the economic point of view, because mRNA drugs, unlike traditional drugs, if the technology to succeed, is likely to avoid patent drugs already on the market, the use of this new technology to develop the targeting a variety of mature mRNA drug targets, it is a very big market.

From a technical point of view, mRNA drugs do not cause cancer and risk mutation, which has a great advantage over gene therapy. And because mRNA is metabolized faster than gene therapy, patients may need only one or several treatments. Patients need to continue to use mRNA drugs (except vaccines), which will also enable them to make long-term profits.

If Bancel is willing to consider the public interest, the technical characteristics of mRNA drugs also enable them to get involved in rare diseases and develop drugs for these diseases. It’s very similar to gene therapy.

After the talks, Bancel fell into deep thought. Although the research background of Bancel is not strong, he can clearly feel the value of the technology. His brain is racing, thinking about Moderna’s scientific and commercial potential.

Soon after, Bancel called Afeyan to tell Afeyan he wanted to join the company. He said he would probably never forgive himself if he refused the job and refused to run a company that could become the next genentech.

On the outside, Moderna’s corporate building is just a four-story brick structure, not a place for top scientific research. Parts of the building and the basement are the company’s laboratories. Bancel soon filled the laboratories with scientists, and their task was to verify and optimize the mRNA technology.

You might think that Moderna is ready to change the world for the benefit of all humanity, and it will be the next gene teck.

Ha ha.

Patent concerns

The concept of mRNA therapy is really simple, if you look at it purely from a business plan. Many diseases of the human body are caused by the inability of the patient to produce enough specific proteins, or defects in the proteins produced, leading to the formation of the disease. In this case, the doctor can inject the mRNA drug into the patient, which can be translated into the corresponding protein after the mRNA is transferred to the cell, thus achieving the purpose of treating the disease.

Unlike gene therapy, this approach does not require a change in the patient’s genome. And while it may be possible to produce some of the proteins needed in some patients by recombinant DNA technology, this is usually limited to some exogenetic molecules. The advantage of mRNA is that it can produce proteins that work inside the cell.

The problem is that Rossi is not the first scientist to try this strategy, and Rossi’s technique is not very original.

Some researchers in the early 1990s have shown that injecting mRNA into mice or rats can induce the production of corresponding proteins in mice. But the protein expression is very low, and mRNA can only be expressed in very short time.

In addition, mRNA itself is very unstable and difficult to develop into drugs. A few years later, scientists discovered that the laboratory’s synthetic mRNA could trigger an immune response after an injection, creating a more dangerous inflammatory response. As a result, some researchers have begun to try to modify the structure of mRNA to prevent mRNA from producing an immune response when injected into the body.

These studies are also the basis for Rossi’s iPS experiments. In order to avoid the inflammatory response, Rossi and Warren use pseudo uracil and 5-methylcytosine to replace uridine and cytidine. Although Rossi’s experiments were successful, there was a big hidden danger. Because the strategy actually came from Katalin Kariko of the university of Pennsylvania and Drew Weissman.

In 2005 and 2008 two article, Katalin Kariko and Drew Weissman were confirmed in mice in vitro and in vivo, using a false uracil nucleoside and 5 – methyl cytosine nucleoside is good to avoid cells to identify the mRNA molecule and cause inflammation. And in 2005 they filed patent applications for the technology for therapeutic purposes.

Kariko and Weissman, who founded a company called RNARx, also received nearly $900,000 in funding from the U.S. government. They had in experiments in mice and monkeys, confirmed that the periodic injections of mRNA drugs can improve the level of the expression of erythropoietin, and erythropoietin can be used to treat certain types of anemia.

But the company’s commercialisation came to an abrupt end because of a patent dispute between researchers and the university of Pennsylvania. Eventually the university of Pennsylvania sold the patent to Cellscript. Although Cellscript has indicated that they are interested in developing drugs for treatment based on the patent, they mainly use the patent to produce various applications of nucleotide modification mrnas.

Kariko and Weissman’s patent poses a major threat to Moderna. In fact, at the beginning of the company, the company had a clear understanding of the patent dispute. Flagship in 2010 of an internal report is very clear to them read, if researchers cannot find false uracil nucleoside and 5 – methyl cytosine nucleoside of other modification strategies, they may have to rely on the university of Pennsylvania’s patent authorization to support the company’s technology.

Moderna is also trying to circumvent the patent risk, and that responsibility falls to JasonSchrum, the company’s first employee. Most of the nucleoside analogues tested by Schrum were not able to replace the pseudo uracil nucleoside and 5-methylpyrimidine nucleoside. But in the end he managed to find a compound, 1- methyl pseudouracil. In 2014, Moderna received a patent authorization for a variety of nucleosides, including 1-methyl pseudouracil.

But the university of Pennsylvania and other companies that conduct mRNA treatments also have a large number of patents in the field. Because companies in the field of mRNA therapy rarely disclose their technology, many companies do not understand the progress of other companies in the field, and there may be disputes over intellectual property rights.

Although Moderna has a patent risk, Moderna’s early investors were not worried. Because they feel that a company that can bring huge breakthroughs to the industry must have the strength and the financial resources to put it all together.

Modified nucleoside chemistry, however, is only one part of the construction of mRNA drugs, Moderna faced another problem is the more deadly, that is to figure out how to let mRNA precisely into certain cells in the body as well as the particular organization. It can be said that this problem is also the most important factor restricting the development of the technology.

problems

For mRNA drug delivery, the difficulty is mainly in two aspects, one is to reach enough cells, and the other is to achieve enough protein net expression.

Many types of cells can spontaneously ingest exposed mRNA and accumulate in lysosomes by endocytosis, but only a small fraction of the mRNA can enter the cytoplasm. For most cell types, the active uptake of mRNA is not only very inefficient, but also very easy to reach saturation at low concentrations. In addition, exposed mRNA is also easily degraded by RNase. Therefore, direct use of exposed mRNA is not feasible, and appropriate strategies must be found to help mRNA transfer to intracellular transport.

In fact, when Moderna was founded, Langer and Bancel said that Moderna was still very small and did not have enough funds to build a drug delivery system. Only external cooperation could be sought. At the time, Moderna looked at about a dozen technical platforms for the delivery system. One of the platforms belongs to Arbutus, but Moderna does not choose Arbutus, but from Acuitas to get access to the technology. Acuitas is a very small company, small to his global headquarters in the CEO’s usual home.

Another problem with the mRNA delivery system, which is the control of protein expression, is very difficult to solve. Although lipid nanoparticles can protect mRNA from extracellular enzyme degradation, it is still very difficult for chemists to develop such a delivery system. Because if the dosage is too low, it’s not enough to produce enough protein to treat the disease, and if the dose is too high, it can be toxic.

Moderna scientists are certainly aware of the difficulty. So they searched the medical literature for diseases that only needed a small amount of protein to be able to achieve therapeutic purposes, so that they could avoid the problem of toxicity caused by excessive doses.

But it’s actually very, very rare. Moderna eventually found a rare disease called crigler-najjar syndrome, which is about one in a million. The disease is probably one of the most treatable diseases Moderna feels.

Crigler-najjar was a very important research project within Moderna. But even Moderna has failed to show that it works.

JP Morgen health industry conference in 2016, Bancel in a crowded room talking about Moderna bright future, he promised with Alexion Pharmaceuticals to jointly develop medicines to treat Crigler – Najjar will in clinical research in 2016.

In a number of public occasions, Bancel has promised that Moderna will promote 100 drugs through mRNA technology over the next decade, and the crigler-najjar drug will be the first.

However, the preclinical data of this drug are too poor to meet the safety requirements of clinical trials. If the treatment is too weak with a low-dose drug, the drug will cause a toxic reaction in the laboratory animal when the dose is repeated.

So when Moderna was looking for a new and better dosage form, the drug ALXN1540 was developed indefinitely. At the 2017 JP Morgen health industry conference, Bancel said nothing about the progress of the project. In July 2017, Alexion suspended cooperation with Moderna.

Because of the project’s setback, Moderna has shifted its focus to other areas of research, focusing on a range of vaccines. Vaccine is probably mRNA therapy is the area where the easiest way to success, for the moment, due to various technical limitations of mRNA is only suitable for those short-term use is enough to reach the purpose of healing and prevent diseases. This is also to reduce the risk of toxicity caused by the delivery system itself.

In fact, the mRNA vaccine has many advantages over conventional vaccines and DNA vaccines. As mentioned above, because mRNA is not infectious, nor does it have genomic integration, there is no risk of infection or insertion of mutations.

Secondly, mRNA can be easily metabolized by normal cell processes, and can regulate the half-life of the body through various modifications, and its production cost is relatively low. For these reasons, the mRNA vaccine has developed very rapidly over the past few years.

Although Moderna has been reluctant to publish the company’s experimental data publicly, Moderna finally published a long-awaited paper on the Cell in February 2017. Before the clinical experiment results show that the company’s mRNA can protect mice against Zika virus infection, all mice were exposed to the virus in the control group of 42 days after death, and accept the Moderna mRNA both experimental mice live vaccine.

Last year Moderna published a clinical data on a flu vaccine. In experimental study while the data is not the problem, but actually Moderna these projects there is still a big risk, because Moderna does not have these mRNA vaccine drug delivery technology patents.

As mentioned above, the technology of the patent right belongs to actually Arbutus, but from another company authorized by the Arbutus Modera Acuitas got the patent authorization, as for Acuitas have rights to authorize Moderna using this technology, it is very controversial.

However, in addition to the controversy of patents and the difficulty of scientific research itself, Moderna’s corporate management model also has a big problem, which will limit the development of the company.

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