The world has stepped into the golden age of life sciences. The constantly outpouring monoclonal antibody drugs have get the venture capitalists satisfactory returns, and those adventurers now start to focus on the field rarely touched in drug inventions: research of mRNA therapy, to treat genetic diseases, cancers, and infectious diseases based on mRNA. Moderna Therapeutics is a global leader in this technology.

Moderna is now using lipid nanoparticles (the top circle in the figure) to shuttle mRNA (the orange-yellow part in the figure) into cells (bottom right in the figure), to translate it into therapeutic proteins (bottom left in the figure).

Let’s return to April 2018. Dozens of venture capitalists attended an investment meeting launched by Moderna Therapeutics in a Marriott Hotel conference hall in Massachusetts. They gathered to listen to Moderna Therapeutics’ introduction of a great project that could be fostered into a "unicorn" in the future. The technology platform of the company was studying injection of carefully designed mRNA into human body to prompt the body to make its own "medicine" to cure diseases. The concept has attracted billions of USD in funding at the meeting.

Stephen Hoge, CEO of Moderna, explained to investors in an interview, "Why are we so passionate about mRNA?" He explained, "In fact, all life that we know flows through mRNA. ... In our language, mRNA is the software of life."

 (Note: mRNA is a key substance with DNA genetic information; it decides the amino acid sequence of body’s peptide chain, and regulates various components that eventually produce human body.)

 "Our ultimate goal is to put mRNA that can cure diseases into human body, to make it form a drug factory inside you. It will make diseases achieve self-cure inside systemic circulation. We will no longer rely on external small molecule or macromolecular monoclonal antibody drugs."

The idea Dr. Hoge was selling seems straightforward, but it is in fact not. When modified mRNA is injected into the body, it triggers virus-detecting immune sensors. That event causes cells to shut down therapeutic protein transcription, thus "sealing up the factory", and foiling the therapy. This is a challenge that has long troubled mRNA delivery experts.

 "Moderna now employs about 600 people, the majority of them scientists, and spends enormous sums—over USD 450 million in the past five years—learning how to make and improve its mRNA therapies. This year, the firm will invest another USD 100 million, and add USD 500 million in the future."

Hoge said at the meeting, "It’s an astonishing sum for a company that is still years away from a marketed product. But what I see is the unprecedented enthusiasm of you siting in front of me. I will get ready for the clinical trial of mRNA therapy using the USD 100 billion received this year."

 "Because we don’t want to develop a drug or therapy just waiting to be acquired by big pharmaceutical enterprises. We want to bring a disruptive unicorn to the drug industry, like Amgen, Biogen, and Genentech, did when they began developing protein therapies called biologics in the eighties. Biologics are now the segment with the fastest-growing profits of the drug industry. We believe mRNA could replace them all. This is a 20-year job. We believe we are just starting."

Hoge shouted on the site, "You could ultimately use mRNA to express any protein and perhaps treat almost any disease. It is almost limitless what it can do."

Moderna announced the exciting results that evening; they invited academic experts who had doubts, showed to them some basic academic studies as to how to convert mRNA into product, and how to use mRNA in the rare genetic diseases, cancers, and infectious disease vaccines, which excited the investors on the site. They saw the possibility of therapeutic mRNA development. Moderna completed USD 1.7 billion financing on the site that evening.

Next, let’s see the birth of Monderna:

In 1990, University of Pennsylvania scientist Katalin Karioko proposed using mRNA as an alternative to DNA-based gene therapy. "DNA’s effect in changing human gene is permanent, but mRNA is more flexible and offers a temporary fix", Karioko reasoned it would alleviate some of the long-term safety concerns surrounding gene therapy.

But nobody was interested at that time, because mRNA was difficult to preserve. Scientists could isolate only small amounts of mRNA, which was then easily destroyed on skin and in the air. And direct injection of mRNA in animals triggered immune reactions thereof. The idea was not as safe as Professor Kariko had hoped. And then she turned to other research projects due to lack of fund support.

But this idea had been in the brain of Professor Karioko. In 2005, she and her colleague Professor Drew Weissma conducted another new idea experiment. They replaced one of mRNA’s four building blocks with a slightly modified adenosine. Amazingly, the modified mRNA evaded immune sensors. (Immunity 2005, DOI: 10.1016/j.immuni.2005.06.008)

 "We submitted that for a patent, and academic intuition told us this discovery might get us very closed to the first therapeutic RNA," Drew Weisseman recalled.

In 2006, excited Karioko started her own mRNA therapy company, but her start-up quickly dissolved because the technology was too cutting-edge to receive funding.

However, the discovery of Karioko still received much attention in the academia. Scholars began to copy Kariko and Weissman’s trick in their labs. In 2010, Harvard University Professor Derrick Rossi used modified mRNA to encode proteins that reprogrammed body cells into embryonic-like stem cells, and received investment of Flagship Pioneering to set up a biotechnology company. After modified mRNA injected into mice could successfully produce proteins, the project and company were resold by the investor, but a part thereof was preserved to become the present Moderna.

In 2013, Professor Rossi used mRNA to encode vascular endothelial growth factor (VEGF) in an experiment. Due to the action of modified mRNA, the VEGF that originally would not exist for a long term in mice lingered there, making enough of the protein to improve the mice’s damaged heart tissues (Nat. Biotechnol. 2013, DOI: 10.1038/nbt.2682).

This experiment formed the backbone of Moderna. AstraZeneca immediately cooperated with it in the same year to replicate the experiment in mice and pigs. From then, Moderna began to establish cooperation with other pharmaceutical companies such as Boehringer Ingelheim and Eli Lilly, with company valuation reaching USD 7 billion.

Moderna has published 2 new articles about mRNA application recently

Mol.Ther.2018，DOI：10.1016 / j.ymthe.2018.03.010

Nucleic Acid Ther。2018，DOI：10.1089 / nat.2018.0734

Hoge believes that if they could solve：

1. avoiding an immune reaction

2. safely shuttling the modified mRNA into the appropriate cells

3. and making sure the mRNA yields enough protein to have an effect, those three problems,

we will see mRNA therapy appear in new disease therapeutic regimens before long, which will be a field beyond the reach of the present monoclonal antibody drugs.

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