It has been several weeks since I came back from Berlin. I was visiting the international mRNA health conference, where I presented our latest development in the mRNA therapy field. Unlike the USA and Europe, mRNA research in Australia is still a young concept. As far as we know, we are probably one of the only groups in Australia who are actively working on mRNA therapy. On my way back to Australia thinking of all the great discoveries I just witnessed in the conference- I had a thought. I must write about mRNA therapy, so more people can know about it. Because when mRNA therapy reaches its age, it will touch most of us.

So what are mRNA and gene therapies and how do they work?

To understand this new class of therapies, we must first understand what makes up mRNA and gene therapies. These molecules are known as nucleic acids. In our cells, there are two major types of nucleic acid molecules: Genomic DNA and mRNA. These carry the manual for all the instructions your cells and body need. They are the code for life. The basic principle of traditional gene therapy is to insert or add a DNA molecule, with specific “designed” instructions and is “translated” by your cell as a protein. In the case of gene therapy, it treats people who lack that protein. mRNA, also known as messenger RNA, is naturally found in all our cells. mRNA is responsible for carrying out a message from the DNA that lies inside the nucleus to the cytoplasm. In there, the proteins are made from the mRNA sequence in a process known as translation. So mRNA therapy uses mRNA molecules instead of DNA molecules, thereby bypassing the need for DNA and simplifying the process (See the figure below).

Nucleic acid therapy, whether it is derived from mRNA or DNA, is a transformational concept in medicine. In contrast to conventional drugs- small molecules acting on a protein or a “target” inside your body- nucleic acid therapy instead instruct your body to make or break the proteins inside your cells at a more fundamental level. You could imagine your DNA and mRNA as the operating program system (OS) for life. Much like computer OS, mRNA therapy can reprogram your body to produce its own therapies. An intriguing concept, indeed.

And what are the uses of mRNA therapy?

Back to Berlin’s conference, many academic and biotech groups presented a wide range of medical applications using mRNA. We and others have envisaged, many times, the range of applications mRNA therapy can have.

Given the mRNA inherent “programmability”, it’s relatively easy to adjust the sequence of mRNA to make, theoretically, any therapeutic protein. This means it can cover a wide range of diseases. Examples of applications that have gone into clinical trials (i.e. trialled in a small number of humans) are cancer immunotherapy, viral vaccines and enzyme replacement therapy for the liver. But the list, as we all expect, won’t stop here. In the context of the human application, many groups and biotech companies presented impressive findings, but these results are still early.

Why is Biotech building mRNA tech?

Effectiveness: Conventional DNA gene therapy needs to overcome many challenges before it becomes a therapeutically viable option. For DNA gene therapy to be active, it requires to reach not only the cell but the very nucleus inside that cell. This is an incredibly difficult task given that our nuclei have evolved to prevent any foreign DNA from entering (Think viruses!). While mRNA therapy shares some of the difficulties of traditional gene therapy, it requires to reach only the cytoplasm of the cells, not the nucleus. Arguably, this is a simpler technical challenge compared to DNA therapy.

Safety: This is the second most important factor facing the field today. While viral gene therapies have been somewhat successful recently, mRNA provides three main advantages over viral gene therapies. The first is how long mRNA lasts. Unlike viral gene therapies which may last months or years, traditional mRNA last for only a short period, no more than a week or two. In the case of overdose, a real possibility with any form of medicine, mRNA overdose problem can last only for a couple of days. This is far more tolerable than an issue that sticks for a very long time- a theoretical possibility with the viral gene therapy. Secondly, the nature of mRNA (i.e. being an RNA) prevents it from integrating into your genome (a DNA). Genetic integrations using viral gene therapies, while a rare event, can have a devastating effect if the integration was placed in the wrong spot in your genome. The third safety concern comes with our immune system. Our immune system has a low tolerance for viral gene therapies because these therapies are delivered by a virus (We call it a viral vector). Our body will attack not only the virus carrying the therapy but possibly the cells that the virus reaches. Although there have been improvements to reduce the viral vector problems, mRNA therapy uses an entirely synthetic combination of materials that are well-tolerated in humans. And the chances are far lower for developing a long-lasting problematic immune reaction.

Affordability: Today, the cost of medicine is a significant concern for patients and governments alike. As the pace of new medical innovation is accelerating, new technologies to produce those medicines safely and in sufficient quantities have not caught up yet. New gene therapies based on viral vector called AAV have a gigantic price tag ranging from $750k -$2 mil USD (1,2). The reason for the enormous price comes, in part, from the difficulty of manufacturing safe viral gene therapy and from the lack of clarity on the cost-benefit balance by marketing companies. Since viral gene therapies are likely to last for years, the price for such medicine has unfortunately skyrocketed to compensate for a “one-shot” approach. mRNA therapy, on the other hand, has a cheaper production price-tag and can be given, regularly, just as conventional medicins. This will aid a more straightforward pricing plan at least in the near future.

So, when will mRNA become mainstream?

Some aspects of mRNA are still under thorough testing, but the development the field has seen in the past five years is mind-boggling. mRNA could be as effective as viral gene therapies but safer and more affordable. Yet many challenges, for example, delivering to different cells in our bodies must be improved if this new class of medicines is set to reach the masses.

[1] Raymond J. March. 2019, Why This New Gene Therapy Drug Costs $2.1 Million? https://fee.org/articles/why-this-new-gene-therapy-drug-costs-21-million/

[2] Bill Cassidy. 2019, How will we pay for the coming generation of potentially curative gene therapies?https://www.statnews.com/2019/06/12/paying-for-coming-generation-gene-therapies/

**note: the title was edited because it caused confusion in technical definition of what gene therapy is: a functional unit. Reading the article clearly demonstrate the difference between the two. No other edits were issued.