What We Need To Unlock Next-Generation mRNA Therapeutics
By Jake Becraft, cofounder and CEO, Strand Therapeutics
With the success of the mRNA vaccines against the Covid pandemic, researchers have gone from saying mRNA could be potentially useful to having an incredibly large data set on functionality and efficacy in humans. Imagine a world where we can cure cystic fibrosis by replenishing the protein in the lungs that helps clear out mucus or where we stop cancer in its tracks by coaxing tumor cells to produce immune cell-activating proteins that lead to their own destruction by the immune system.
These achievements will be the result of the natural evolution of mRNA therapeutics. As we’ve learned more about biology, the therapeutics we’ve produced have become more sophisticated, accurate, and precise. Due to their ease of manufacture, nimbleness, and programmability, mRNA therapeutics have the potential to address some of the most difficult challenges faced by existing DNA and protein-based therapeutics, such as limited deliverability and reduced therapeutic index.
At Strand Therapeutics, we’ve been working on programmable mRNA therapeutics — applying mRNA’s utility beyond vaccines and programming molecules to do additional useful actions, like turn on in specific cell types or at specific times. In this article, I share some of my learnings working in the space and some practical thoughts for the future of the field.
Shortening The Design-Build-Test Cycle
mRNA is an incredibly nimble platform for drug discovery and development. Unlike protein delivery to the human body, the mRNA payload being delivered is simply an instruction manual. It’s easy to rapidly iterate through different versions of mRNAs for different protein variants or even types of proteins. In fact, in the best functioning mRNA development labs, the iteration cycle on each new design takes only a couple of weeks, compared to two to four months for iterating on an engineered virus or protein biologic.
This compounds over a two-year development cycle, creating exponentially higher build-test-learn cycles. With the traditional few months' wait time, you might be able to go through eight generations in two years. With mRNA, you can go through more than 80 generations in that same time period — an incredible amount of developmental iteration.
This greatly simplifies and speeds up the manufacturing process. With mRNA therapeutics, the manufacturing process and delivery process to the human body are universal; the only thing that needs to be changed for each new protein is the protein instruction code, which in today’s modern laboratories is a straightforward and quick process.
Thinking Outside The Box To Tackle mRNA Challenges
The developmental trajectory of mRNA-based therapeutics is still relatively recent. A significant amount of research needs to be done to improve our understanding of exactly how these therapies work.
Vaccines have been the coming out story for mRNA because they are delivered via lipid nanoparticles that are injected directly into the muscle tissue. But for targeted delivery of mRNA to work throughout the body, we need a lot more research. Take delivery to the liver as an example. Alnylam Pharmaceuticals is a pioneer in lipid nanoparticles for silencing RNA, and its commercial products mainly deliver to the liver, while Intellia Therapeutics has delivered mRNA molecules encoding CRISPR proteins to the liver. Despite these advances, lipid nanoparticle delivery of mRNA molecules remains limited in use cases outside of the liver and direct tissue injections.
How can we deliver a large enough dose to the tissue without it going to tissues we want to avoid? This problem will only be solved with new thinking. There's a lot of focus around lipid nanoparticles. However, engineering of the mRNA molecules themselves is an equally important avenue of engineering, and one that has been largely overlooked. If we can learn how to think outside the box, controlling not just the lipid nanoparticle but also the specificity and duration of mRNA translation of therapeutic payloads, and then manufacture the molecules at scale and with high purities, the ability of mRNA to be a broad-reaching platform will be supercharged.
What We Need To Supercharge mRNA
Answering these questions requires more fundamental research funding in this space. DARPA, the NIH, and other government agencies in the U.S. and abroad have done a great job of supporting early mRNA research. Strand Therapeutics is a product of DARPA funding we received while at MIT, in the same early programs that also supported Moderna as a young biotech startup. However, we as an industry need even more funding to increase research into some of the fundamental questions around mRNA. Groups like Wellcome Leap are doing just that, as is the Gates Foundation, and the newly announced ARPA-H has already started making inroads here as well. I hope others follow their lead.
Not only will increased funding answer the fundamental questions required to use mRNA-based therapeutics confidently, but with that increased understanding comes increased buy-in from regulatory authorities, particularly for the next generation of mRNA-based therapeutics. COVID-19 and its variants have provided a great proving ground for rapid iteration of mRNA therapies (vaccines). They have also acted as an interesting case study: right now, we have multiple billions of data points of mRNA vaccine efficacy and safety in populations across the world. I don't know if there's a new drug modality in history that has been so broadly utilized and de-risked across the globe so rapidly, due to the necessity of the pandemic response.
What we’ve learned from this is that mRNA is broadly tolerated among patients and is widely effective across patients, across every ethnicity and age group/demographic.
Moving Medicine Forward
Our belief is that mRNA therapeutics will be routine in clinical settings incredibly soon. The rapid development and rollout of the COVID-19 vaccine illustrated what’s possible with an iterative, safe, easy-to-administer therapeutic that also has sufficient financial support and coordination from regulatory agencies. All of this was achieved because the urgency of the pandemic required quick action. But we made it happen. Let’s use this as a launch point for further development of mRNA-based therapeutics so that they can do what they’re capable of: transforming the biotech industry.
About The Author:
Jake Becraft is co-founder and CEO of Strand Therapeutics, which is developing a programmable mRNA therapeutic platform. Becraft co-founded Strand based on his Ph.D. research in biological engineering and synthetic biology at MIT.