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Improvements in R&D, manufacturing, and data sharing will extend platform’s reach.
Although mRNA was thrust into the spotlight by COVID-19, the potential for this emerging therapeutic modality extends far beyond the vaccines that were developed in record time during the pandemic. The second wave of mRNA could usher in preventative vaccines for the flu and a wide range of bacterial and fungal diseases. Some drug developers are working on personalized mRNA vaccines that fight cancer based on genetic mutations found in individual patients’ tumors.
Eventually, scientists will be able to use novel genomic editing tools, such as base editing and CRISPR, in the context of mRNA to edit pathways that cause chronic conditions. Recent proof-of-concept clinical data has shown that a lipid nanoparticle (LNP) containing mRNA encoding for CRISPR/Cas9 can precisely knock out a disease-causing gene in the liver, and treat and potentially cure a rare and progressive disease called ATTR amyloidosis.This is only the beginning, as in vivo gene editing using mRNA can potentially be used within the context of other chronic conditions, such as autoimmune disorders and cardiovascular disease.
The potential for mRNA technology is vast, but to fully realize it, the industry will have to come together to develop new, innovative technologies and production processes. In rapidly bringing the COVID vaccines to market, developers worked with regulatory agencies, contract manufacturers, digital-solutions providers, clinical trial sites, and even their own competitors to compress R&D and manufacturing timelines. Now we need to build on that convergence so we can enable the next wave of mRNA therapies — and bring them to market efficiently.
Here are three key areas that developers of mRNA therapies should focus on to further that effort.
1. Improve mRNA delivery vehicles — The COVID vaccine rush created a huge market for the LNPs that are used to deliver mRNA into cells. LNPs are useful but limited in their targeting ability — they go to the liver primarily. To use mRNA to treat a complex disease, such as pancreatic cancer, developers will need new delivery vehicles that can target only those cancer cell types. And they’ll have to figure out how to deliver much higher doses of mRNA than what’s currently required for COVID vaccines.
Several efforts are underway to develop next-generation LNPs that can safely carry mRNA to a wide variety of cell types, and new technologies are enabling these advancements. Until recently, only a small group of specially trained scientists could design LNPs. Now, thanks to new technology small enough to fit on a typical workbench, any mRNA developer can take a nucleic acid and a proposed lipid formulation, insert them in one end of the machine, press a button and get well-formed LNPs almost instantly. That can shorten the cycle time around experimentation, making it easier and less costly to test a variety of LNP formulations for each mRNA therapeutic in development. And with next-generation microfluidics technology, developers can better control the homogeneity of their LNPs, improving standardization and making it easier to scale up mRNA drugs for large-scale manufacturing.
Developing alternative delivery vehicles is another priority, and exosomes are emerging as a prime candidate. Exosomes are extracellular vesicles that our bodies make and use to deliver nucleic acids to different cell types. Because exosomes represent their origin cells and are naturally stable, they could ultimately be the best vehicles for delivering mRNAs to specific organs.
The science of exosomes continues to evolve, and there are still questions to be answered regarding their toxicity and immunogenicity profile. That’s why developers of mRNA therapeutics should seek out partners early in development who can used advanced techniques for isolating and characterizing exosomes.
One such technology is differential ultracentrifugation, an advanced form of ultracentrifugation that can separate compounds based on density gradient. Recent advancements in this technology have led to increased throughput and reproducibility, improving the accuracy of results.
2. Optimize development and manufacturing —Drug makers can work with their technology vendors to optimize the design of mRNA medicines early in development and then to standardize it. Accelerating that standardization process will help to define the way that these tools are implemented and deployed for clinical development, and eventually for commercial manufacturing.
A good place to start is in the selection of the plasmid backbone that’s needed to make mRNA medicines. New plasmid platforms are available that are smaller than the first generation and free of antibiotic markers that can raise safety concerns. These optimal characteristics can bring down the time involved in both developing mRNA medicines and manufacturing them.
Part of the standardization process is ensuring that all of the equipment used in clinical development is easily scalable, so if early trials are successful, mRNA developers can ramp up the manufacturing process and bring their products to market rapidly.
3. Share data —During the pandemic, the biopharmaceutical industry collaborated with multiple stakeholders to speed mRNA vaccines to market. Data sharing was key to those collaborations.
For example, within days of Chinese scientists posting the genetic sequence of SARS-CoV-2 online in January 2020, Moderna and the National Institutes of Health (NIH) had completed a basic design for an mRNA vaccine. Moderna delivered the first doses of its vaccine to the NIH in February of that year.
The NIH fostered COVID therapeutic development more broadly by providing open-access data and computational tools free of charge to scientists working on combating the virus. And early research results were rapidly disseminated prior to peer review on preprint servers like bioRxiv, boosting transparency and preventing the duplication of research that was likely to fail.
This degree of data sharing must continue after the pandemic to maintain the momentum of mRNA development.
Pharmaceutical developers are often reluctant to share data for fear of revealing trade secrets, but it is possible to strike a balance. For example, mRNA researchers could share advances in analytical techniques that are specific to therapeutic classes but not to any individual product. They could also continue to publish data from mRNA approaches they tried that didn’t work. This data would inform the ongoing effort to extend mRNA’s reach, potentially offering groundbreaking new approaches to infectious disease, cancer, and more.
It’s clear that mRNA medicines have the potential to revolutionize the treatment and prevention of myriad diseases. But to realize that promise, mRNA developers will need to collaborate with industry partners and the scientific community to drive improved processes across R&D and manufacturing. Specifically, they should focus on improving LNPs and alternative delivery technologies, boosting efficiencies across R&D and manufacturing, and sharing data that will drive continued improvements across the industry.
Sadik Kassim is chief technology officer, Genomic Medicines for the Life Sciences companies at Danaher Corporation, which include Aldevron, Integrated DNA Technologies (IDT), SCIEX, Beckman Coulter Life Sciences, and Precision NanoSystems.