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The Bright Future of mRNA

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The concept of utilizing messenger RNA (mRNA) to prompt endogenous production of a molecule that serves a therapeutic – or in the case of vaccines, preventive – purpose is not a novel concept. Over recent decades, mRNA research and development has accelerated rapidly such that, in the face of a public health emergency, technologies and workflows were ready for optimization and scale-up. This preparation enabled scientists to expedite the development and manufacture of the first mRNA-based product authorized for human use, a vaccine against SARS-CoV-2.

Now, it is argued that we are entering a new era of medicine; a “revolution” based on the broad applications of mRNA platforms across various disease areas. In 2021, the healthcare company Sanofi launched its mRNA Centre of Excellence. The center will focus on innovating mRNA platforms to address long-standing therapy challenges in diseases with high unmet need.

Technology Networks interviewed Frank DeRosa, chief technology officer and head of research at the mRNA Center of Excellence, Sanofi, to discuss the “bright future” of mRNA platforms. Having worked with mRNA technology for well over a decade, DeRosa talks in detail about the evolution of the field, how it has overcome challenges such as delivery and large-scale manufacturing, and the barriers that currently prevent its widespread application.

Molly: Can you talk about how the field has evolved over the years in which you have worked with mRNA technology? In your opinion, what have some of the key challenges and breakthroughs been?

Frank DeRosa (FDR): It has been – first and foremost – an extremely exciting field that I have been fortunate enough to work in for many years. mRNA research has continued to grow and expand, such that mRNA itself has really become a “household name”, which is a great feeling knowing that so many of us have worked on it for such a long time.

The field has evolved in many ways, including the applications of the technology, delivery and manufacturing.

First, let’s look at applications. The possibility of using mRNA for both vaccines and therapeutics is described in literature from several decades ago, but this was small and sporadic. The possibility of vaccine applications was an initial focus of some of our peers in the field, for example CureVac and Novartis in the early 2000s, so it is great to see that mRNA-based vaccines have now been achieved, as we now have approved products in this space.

Our experience with this platform here at Sanofi started with a focus on the delivery of therapeutic mRNA for treating rare diseases. That has its own associated challenges, one being chronic dosing – the ability to dose repeatedly. A lot of progress has been made on that front with the ability to re-dose mRNA, most notably using lipid nanoparticles. Prior to this focus, predecessors to the field of mRNA delivery, such as Professor Pieter Cullis at the University of British Columbia Vancouver, showed that liposome/ lipid nanoparticle-based delivery could be useful for the delivery of other nucleic acids, such as small siRNA nucleic acids.

Since recognizing that liposomes/LNPs can effectively deliver mRNA, there have been great breakthroughs in the area of delivery with respect to the understanding of how to package mRNA, how to deliver it to certain organs – both from a single dose as well as a multi-dose regimen – preclinically, and in some cases clinically. mRNA delivery has now progressed through to intramuscular applications in vaccines, as can be seen with the success of approved COVID-19 vaccines, which is fantastic.

The other big breakthrough, which is also an area that Sanofi has focused on, is large-scale manufacturing of mRNA. Historically, it has been very difficult to manufacture mRNA in large quantities. Typically, you would have to buy microgram to milligram quantities of mRNA – enough for say an animal experiment or two – and then would have to figure out how to make more or buy more, which proved expensive.

At Sanofi, when we started working with this platform, we had a heavy focus on rare diseases, chronic dosing and pulmonary applications. When you are using mRNA for pulmonary-based applications, the demand is huge. We were particularly focused on nebulizing the material, and when dosing animals for pre-clinical studies, 99% of the material is blowing past the animal because they're typically inhaling through their nose and the instrumentation used is not the most efficient. You therefore must be able to make a tremendous amount of mRNA as so much of it goes to waste in this context. It forced us here at Sanofi to develop a large-scale manufacturing process. Now you can see this being adopted across the industry, with fast progression in terms of capabilities for manufacturing mRNA at a large-scale, which is a huge breakthrough. It ultimately influences the ability to drive costs down and deliver more doses.

MC: In the pharmaceutical industry, what factors help to shape the decision to pursue a candidate for an indication? Is this process different for “novel” therapeutics, like those that are nucleic acid-based?

FDR: There are a lot of factors involved, some of which are disease specific and others that apply across many different disease areas, from oncology, infectious disease, to rare or chronic disease applications.

There are several questions that need to be asked. Number one: do you believe that your target will be efficacious? Whether you are developing a recombinant based protein, mRNA or a small molecule drug – do you feel that you can have a meaningful effect in the patient population?

Additional questions come from a business standpoint, such as: What is the patient population? What is the size of the patient population, particularly in the case of rare and ultra-rare diseases? This is an important factor, because you must consider whether there is competition on the market. If so, where are they in their clinical trial status? Are they early pre-clinical, or Phase III, for example? Are there improvements that could be made to existing products on the market?

With mRNA-based therapeutics, you can go a little deeper with your analysis. Certain therapeutics, let’s say proteins, can drive an efficacious result, whether it be for an infectious disease or for an alternative application. But can you make that specific drug and deliver it? For example, if you have a very highly hydrophobic protein, such as cystic fibrosis transmembrane conductance regulator (CTFR), it is very difficult to make a drug from a recombinant protein standpoint, because you need to produce it so that it is perfectly folded, active and can be delivered into the cell membrane in the lung. However, if you can deliver the mRNA that encodes that specific protein, the body can do the rest of the work. The body’s own endogenous ribosomal machinery can translate that protein, fold it, glycosylate it and traffic it to where it needs to be delivered. This is a huge advantage to mRNA technology.

It’s a clearly visible advantage, particularly when considering vaccines, where you need to produce a given number of antigens, some of which are easier to make than others. mRNA takes advantage of the endogenous capability to produce the protein in the cell itself, mimicking a protein production factory.

MC: Can you talk about the unmet clinical need in the therapeutic areas that Sanofi is working in, and how mRNA-based therapeutics can help?

FDR: Certainly influenza as an indication and a franchise is very important to Sanofi. Sanofi is a leader here, with multiple technologies, both from an egg-based approach as well as a recombinant protein-based approach. There is extensive “know how” and experience within the organization, which is fantastic, and is just one of the many reasons I am excited to be a part of the Sanofi family.

There are advantages associated with the mRNA platform application towards influenza. Namely the speed at which you can obtain a sequence – let's say from the World Health Organization (WHO) – and be able to produce your desired drug and get it to market. Speed is very important in the influenza market.

Also, there are advantages with how you can produce mRNA from these sequences. For many influenza vaccines, four different antigens, with four different production processes and purification processes are required. That takes time, resources and can be costly. With mRNA, you can utilize the same exact process, no matter what the sequence is, you can utilize the same production process, the purification process and you can run them in parallel. This provides further advantages for speed and of course in reducing costs.

There's also an advantage to using mRNA from a manufacturing foot-print perspective. There is the ability to produce millions of doses in single, relatively small room, such as we do here at Sanofi using our large-scale manufacturing non GMP practises, ultimately reducing the footprint of the industry.

MC: Can you talk about whether it is arguably simpler to progress certain technologies, like mRNA platforms, based on their indication compared to others? Or is it relatively the same process regardless of the therapeutic area?

FDR: There are some similarities and some differences across and within modalities.

In some regards, mRNA technologies can be easier than others. What I mean here is that, if you wanted to screen 1000 different inactivated viruses, that might be hard to do. If you want to screen 1000 mRNA sequences, that’s very easy to do, and very quick. You can do it with extreme ease through high-throughput applications and automation, which Sanofi has and is building out further.

That allows you to create an optimal drug candidate – in theory – in a high-throughput fashion. Again, this is because the technology allows you to do that; you can use the same process to make thousands of different mRNAs.

From a therapeutic standpoint, sometimes it’s a disease–disease comparison. For some diseases, the analytics aren’t there for let’s say the protein, or there isn’t a sufficient animal or efficacy model, and that would make it difficult regardless of the technology.

MC: In your opinion, would the mRNA “revolution” (as some have called it) have occurred regardless of the COVID-19 pandemic?

FDR: Yes, I think it would have happened. I think certainly it would have been a little bit slower, perhaps a longer path because processes were accelerated and ran in parallel. I think we will continue to see improvement and growth and impact with this revolution across other applications, not just infectious diseases.

MC: From the pharmaceutical industry standpoint, when developing mRNA therapeutics/ preventives, what are the greatest challenges that remain?

FDR: There are a few. When you're talking about therapeutics, and in particular chronic-based applications where a patient has to receive a dose every two weeks or every month, there are safety implications with that tolerability. We need to ensure that there is the ability to continue to produce or express the desired protein of interest equivalently after each dose. This is where a lot of progress has been made, but it’s something that you always need to have in mind and a place where I think there is more work to be done.

From a delivery standpoint, I think the field has come a long way. Of the many different types of nucleic acids, mRNA has unique challenges with delivery. With mRNA, we’ve certainly come a long way, but there is still room for further advances there.

What we see, even with the currently available mRNA vaccines – which I like to call “first generation vaccines” – is that there was a “high” reactogenicity.

Some of the COVID-19 vaccines, particularly mRNA-based vaccines, were associated with nausea, headache or perhaps a fever that lasts a couple of days.

With certain marketed vaccines, such as influenza vaccines, you do not typically see that reaction with the standard of care. We need to improve mRNA-based vaccines, and this is a challenge that we are undertaking now to try and improve the reactogenicity profile and lower it such that is compares favorably to the standard of care.

Also, mRNA vaccines that are currently on the market are frozen, which is fine for developed countries under a pandemic setting. For developing countries, these low temperatures are very hard to handle with respect to transporting the vaccine, but the low temperatures are necessary for the mRNA to maintain its integrity.

Sanofi has been making a lot of progress on that front to try and develop a liquid stable mRNA drug product. We think this is imperative for the flu market, with respect to the current standard of care and expectations from healthcare providers and pharmacies, with regards to ease of use and “ready to go” dosing for the public.

MC: What does the future of mRNA-based medicine look like?

FDR: I think the future is bright! Certainly, for mRNA-based medicines and for vaccines. I think we will see more applications on the therapeutic side, whether it be for rare disease, inflammation or oncology.

There are also applications in gene editing, for example using CRISPR-Cas technology. Using mRNA here is arguably a safer approach, because there isn’t a permanent production of the nuclease. Again, it’s a nice way to have endogenous production of a given nuclease with precision, that can hopefully edit the gene appropriately. These are all applications of mRNA that I think have a bright future.

Frank DeRosa, chief technology officer and head of research at the mRNA Center of Excellence, was speaking to Molly Campbell, Senior Science Writer for Technology Networks.