Partnering to Deliver the Next Generation of mRNA Drugs
With over 1000 clinical studies underway, the field of mRNA therapeutics is exploding. To fulfill the promise of this technology, rigorous manufacturing is key. mRNA researchers at The University of Queensland’s BASE facility are leading the charge. To learn more, we talked to Associate Professor Tim Mercer, BASE Director, and Dr. Seth Cheetham, Scientific and Partnerships Lead.
This article is posted on our Science Snippets Blog
The ability to rapidly encode virtually any protein into an mRNA drug is enabling scientists to respond more quickly to emerging infectious diseases, unlock more of the druggable genome, and open up new frontiers in personalized medicine and the treatment of rare diseases. Alongside advances in mRNA technology, rigorous manufacturing and quality control are essential for success. At the BASE facility within the Australian Institute for Bioengineering and Nanotechnology (AIBN) at the University of Queensland, researchers are leading the charge in the design, manufacture and evaluation of mRNA drugs.
Tell us about the BASE facility and what you are aiming to accomplish in your work?
“Our mission at BASE is to provide mRNA to researchers and to commercial partners, so we serve both academic and commercial sectors,” says Tim. “BASE serves as a central facility that supplies mRNA to researchers all over Australia. We have built more than 40 mRNA vaccines, therapies and reagents for use by our scientific, clinical and industry partners. As heads of adjacent research labs at AIBN, both Seth and I also have a much broader vision of the future of mRNA as a drug delivery platform. The role of our research labs is to develop innovative technologies that push the envelope in mRNA drug design and manufacture. So our wider mission is to design, build and deliver the next generation of mRNA drugs.”
Why is mRNA generating such excitement right now as a platform for drug delivery?
“While researchers have been working on mRNA therapeutics for the past decade,” says Seth, “the COVID-19 pandemic really brought this technology into the spotlight. We saw the power of mRNA as a platform to accelerate development and deliver new vaccines in record time, and then to rapidly scale up production to meet rising global demand.
"From a technological perspective, one of the reasons this new platform is so exciting is that mRNA-based drugs fight disease in a way that is fundamentally different from anything that’s gone before."
Rather than injecting a therapeutic protein into the patient, with mRNA we harness the patient’s own cells as factories to produce the final protein product.
Dr. Seth Cheetham, Scientific and Partnerships Lead at The University of Queensland's BASE Facility
"Not only does this bypass many of the challenges with the design, manufacture, and stabilization of bioactive proteins, it also opens up completely new therapeutic possibilities. So far, we’ve only just scratched the surface of what can be done with mRNA technology."
“The versatility of this platform and its scope for new advances is truly astounding,” Tim comments. “In essence, you are decoupling the manufacturing process from the drug that’s delivered. So as a platform, mRNA is extremely versatile, because in principle you can encode any protein in the mRNA and deliver it to any cell in the body, where it will then produce the drug that you want—whether that be an antibody, a vaccine, an enzyme, a replacement protein, or a chimeric antigen.”
How is mRNA changing drug development and manufacturing paradigms?
“The beauty of an mRNA platform is that you don’t have to redesign the workflow every time you want to produce a new mRNA product,” says Seth. “This is one of the reasons mRNA vaccines for COVID-19 were first to market. Researchers were already working on mRNA-based vaccines and therapies to address other targets, so the infrastructure and the platform manufacturing processes were already in place. They were able to quickly swap out the construct they were working on and replace it with mRNA encoding the SARS-CoV-2 spike protein.”
Process standardization is a game-changer
Associate Professor Tim Mercer, BASE Director at The University of Queensland
“If you can make one mRNA successfully, you can make any mRNA with essentially the same process. That’s a major time advantage compared to biologics manufacture, where the workflow needs to be redesigned, optimized and validated for each new product.
"mRNA manufacture is also much faster and less complex than for biologics. In vitro synthesis of mRNA takes only a couple of hours, whereas production of a protein biologic can take from a few days to several weeks or even months, depending on the system and the desired yield.”
How scalable are mRNA platform technologies?
“Another benefit of the mRNA platform is its incredible scalability,” says Seth. “The world needs an estimated 22 billion doses of mRNA vaccines to bring the pandemic under control in 2022, and fortunately mRNA technology is up to the task. At the other extreme, an mRNA process can be scaled down relatively easily and cost-effectively to produce just enough of a vaccine or therapy for a handful of patients, or even a single individual. This makes it more feasible, both economically and practically, to address rare diseases and develop personalized drugs such as cancer vaccines.”
What challenges are you currently tackling in mRNA manufacturing?
“As the field expands with new mRNA technologies, targets and applications, there’s a lot of scope to optimize and improve mRNA manufacturing,” says Tim. “That includes not only the in vitro synthesis and bioprocessing steps, but also the analytics used to measure the integrity and purity of the mRNA products. We’ve recently developed a new quality test for mRNAs based on a novel next generation RNA sequencing approach. When integrated into the BASE manufacturing workflow, the test will allow rapid assessment to determine whether mRNAs have the correct length and sequence, whether modified nucleotides are correctly incorporated, and whether the 5’ cap is present. Because the analysis is done in real-time and is very sensitive, the test will support in-process QC, as well as validation of mRNA quality after storage or transport.”
How is the research collaboration between BASE and Sartorius helping you address these challenges?
“Currently, we’re applying technologies that we’ve developed, such as the quality test Tim mentioned, to optimize in vitro mRNA synthesis,” says Seth. “This involves testing a large number of different conditions to determine how different parameters affect the reaction. Sartorius equipment and Design of Experiments software is integral to this work. With the Ambr® 15 system, we’ll be able to analyze up to 48 mRNA sets of conditions in parallel in 10-15 mL working volumes, monitoring environmental temperature and pH as well. With Sartorius Design of Experiments to guide us, we can explore the impact of all the different factors and tolerances at a detailed level, with the minimum number of experiments. Downstream of mRNA synthesis, we’re also refining the mRNA purification process. The Ambr® Crossflow for tangential flow filtration (TFF) allows us to run up to 16 trials in parallel to evaluate the impact of this purification step on the quality and recovery of mRNA from in vitro synthesis.”
What’s next on the horizon for mRNA manufacture and your partnership with Sartorius?
"The field is massively expanding and diversifying, with more exotic mRNA technologies like circular RNAs and self-amplifying mRNAs showing great promise,” says Seth. “While these new approaches will come with their own complications in terms of synthesis and purification, they will offer some exciting advantages over standard mRNAs."
To support that, we envision a long-term partnership with Sartorius so we can continue to advance mRNA manufacture in line with these technology leaps.
Dr. Seth Cheetham, Scientific and Partnerships Lead at The University of Queensland's BASE Facility
“That’s right,” adds Tim. “While everyone appreciates the amazing science behind advances in mRNA technology, it’s worth remembering that manufacturing is just as crucial for the success and cost-effectiveness of these novel technologies. Over the next five to 10 years, I think we’re due to see a big return on all the interest and investment that’s been focused on mRNA. Ultimately, through our collaboration with Sartorius we hope to significantly improve quality and cost-efficiency of mRNA manufacture. These efforts will hopefully make potentially life changing new vaccines and therapies more reliable and accessible to patients around the world.”
