For decades, scientists have dreamed about the possibilities of using custom-made messenger RNA (mRNA), the product of DNA, to treat diseases. Researchers understood mRNA as a recipe book that directs protein production for the body’s trillions of cells. The dream was to make customized mRNA medicines such that when injected into humans, any cell in the body could be transformed into an on-demand drug factory. One could create any protein desired – antibodies to protect against infection, enzymes to reverse a rare disease or proteins to help the body repair damaged hearts. But turning scientific promise into medical reality has taken a long time and proven much more difficult than many assumed (Nature Article on the History of mRNA vaccines).
This changed in the last two years as RNA medicines, in the form of novel mRNA vaccines, captured the world’s attention when it proved extraordinarily effective in protecting against severe COVID-19. This reinvigorated interest in the great potential of RNA therapies, causing investments and talent to flow into RNA-focused companies that is fueling a wave of RNA innovation in vaccines and therapeutics.
Prior to the pandemic, RNA treatments were focused on rare genetic diseases with small target markets. Today, more than 800 RNA medicines are in clinical development for more common indications in major areas such as oncology (vaccines and therapies), infectious diseases, cardiology, ophthalmology, and neurology.
RNA medicines are poised for rapid growth, but there are still key challenges that we need to overcome to unlock RNA’s full potential.
Safe and Effective Delivery of RNA
Delivery is a long-standing challenge for RNA therapies. Because RNA is inherently unstable, it needs to be stabilized and protected from degradation in the body. RNA is also highly charged and has its own potential toxicities and must be modified or shielded from the body until it reaches its target cells. RNA itself does not specifically target cells, and untargeted RNA could have reduced efficacy or cause toxicity if it enters cells that are not its intended target.
Chemical modification of RNA itself helps to stabilize it and reduce safety risks to some extent but is insufficient. Additional delivery technologies are required to deliver RNA safely and effectively. An ideal RNA delivery system should be easily manufactured and scalable, comprise of safe components with biodegradable chemistry, customizable to efficiently deliver different RNA payloads and allow precision control of tissue targeting and be non-immunogenic.
Some RNA-based gene therapies that in development also use modified viruses as drug delivery vehicles. Though powerful for RNA delivery because of their ability to enter cells efficiently, viral vectors elicit a strong immune response that can reduce therapeutic efficacy as the therapy is rapidly eliminated by the immune system. More importantly, this immune reaction leads to safety concerns and prevents repeat dosing with the same viral vector, which limits their utility since many gene therapies don’t work completely the first time and require multiple doses.
Another potential delivery vehicle being explored are exosomes, which are lipid membrane-enclosed vesicles that are secreted by most cells. These vesicles can have minimal immune clearance. Some companies developing exosomes include Codiak BioSciences, with its engExTM platform, and Evox therapeutics, which has partnered with Eli-Lilly to use their DeliverEXTM exosomes to deliver a siRNA drug to the brain.
The technology used most widely for delivering RNA medicines are lipid nanoparticles (LNPs). LNPs are used in mRNA vaccines and most RNA therapies in clinical trials. However, LNPs lack targeting and are themselves highly immunogenic. Immunogenicity can be a feature for vaccines but are an unwanted side effect in other RNA therapeutics. Challenges with dose optimization and immunogenicity of RNA therapeutics, mostly formulated with LNPs, has resulted in high failure rates in Phase II and III trails.
Many RNA therapeutics companies are trying to improve on LNP technologies by synthesizing libraries of LNP formulations with varying levels of four basic lipid components. However, they mostly still contain highly charged cationic/ionizable lipids and polyethylene glycol (PEG) that result in cell toxicity. As such, a complete reformulation of LNPs may be required.
SiSaf, our portfolio company in the UK, has solved many of the problems with current LNP technology with their proprietary Bio-CourierTM technology, a platform of silicon-stabilized hybrid LNPs that greatly improve RNA stability, safety and targeting. The company has used Bio-CourierTM to develop a deep pipeline of RNA therapeutics, and recently presented positive pre-clinical data targeting a rare bone disease, Osteopetrosis, with a proprietary Bio-CourierTM-formulated siRNA drug. They showed that their non-viral, Bio-CourierTM LNP delivery system can efficiently target the bone and more importantly, not elicit any immune response, enabling repeat-dosing of the therapy with no side effects.
Costs and Ease of Distribution
Another major hurdle to broadening RNA therapeutics’ impact is its high cost to manufacture and distribute, stemming from RNA’s instability and the challenges that poses to storage and transportation. Viruses are difficult to scale and expensive to manufacture. Exosome manufacturing technology remains limited at scale. We have witnessed first-hand the onerous requirement for ultra-cold chain logistics to transport and distribute LNP-formulated mRNA Covid-19 vaccines. Delivery technologies that can eliminate this need would greatly increase accessibility and bring down costs.
Some strategies being explored to ease transportation and storage requirements include freeze drying or lyophilization. However, keeping the RNA structure intact whilst removing water is no small feat. Advances in next-generation LNP platforms can further enhance this process. For example, the high structural integrity of SiSaf’s silicon-hybrid delivery vehicle maintains RNA integrity even at room temperature and allows for freeze drying.
The future of RNA
With RNA ascendant in popular imagination, the global RNA therapeutics market is projected to reach more than USD$25 billion by 2030, RNA technologies are expected to make large strides in the coming years.
In 2022, more than two dozen new RNA therapeutic candidates are expected to enter the clinic for the first time. A dozen therapies will be studied in larger Phase III studies, including seven siRNA candidates such as Novartis’s Inclisiran and Sanofi’s Fitusiran. Just this past July, Alnylam Pharmaceuticals received FDA approval for Amvuttra, which is an RNAi therapy for a hereditary Amyloidosis. We expect to see even more approvals for RNA therapies in the near future.
We are ushering in a new era of mRNA-based vaccines, expanding beyond SARS-coV-2 to target other infectious diseases like influenza, RSV and malaria. This has also accelerated research on mRNA vaccines used to treat cancer.
Besides advances in RNA delivery techniques crucial to the success of this class of therapies, other RNA technologies to watch are developments in self-replicating RNA medicines. These are RNA outfitted with the genetic code that some viruses use to turn cells into reproduction factories. That way, RNA that enters the cell can make more copies of itself and the therapeutic effect can last for a much longer time. This could allow for smaller and less frequent doses with reduced side effects. There are also companies trying to engineer circular RNAs, which are much more stable than mRNA.
The story of RNA therapeutics has just begun, and the next chapter is going to be as exciting, if not more so, than the promising start we have experienced with mRNA vaccines.
