To improve or accelerate clinical development, mRNA therapies leverage synthetic messenger RNA to instruct cells to produce specific proteins, and thus offer a versatile platform for treating a wide range of diseases. RNA is synthesised by in vitro transcription (IVT) from a DNA template encoding the sequence of interest, including untranslated regions (UTRs) – sections of messenger RNA (mRNA) that are transcribed but not translated into a protein. The quality of the mRNA (e.g. target sequence, length, and purity) is a key determinant of translation efficiency, stability, and immunogenicity.
All these factors impact the safety and efficacy of the mRNA-based therapeutic. It is essential, therefore, to work with partners with the experience and capabilities to optimize IVT and purification steps to maximize both mRNA yield and quality.
CPI and Quotient Sciences have formed a joint venture to integrate capabilities for end-to-end mRNA manufacturing. This shared expertise helps develop, manufacture, and perform QC testing and characterisation of both mRNA drug substance and bulk formulated lipid nanoparticles (LNPs) in a single site. Such approaches ensure that the knowledge built during development is at hand as a program moves into GMP production.
By maintaining clear and open communication throughout the process, each program can be delivered by multidisciplinary project teams of experts contributing, coordinating, and scheduling as programs advance from RNA synthesis to clinical dosing.
Successful partnerships do not end there. RNA therapies are no different to other modalities in that prior to dosing to humans, a comprehensive non-clinical safety package needs to be collated to ensure safety. Working closely with regulatory authorities addresses some of the unique challenges associated with these medicines, and when a therapy developer’s expertise includes supporting the development of draft guidelines on individualized mRNA cancer immunotherapies, that’s when the hard work and cooperation pays off.
A collaborative approach should always be taken with regulatory bodies, who – in turn – should remain open to dialogue and contribute their long histories of supporting developers through Scientific Advice meetings. The regulatory principles in the new MHRA guideline that we helped develop, for example, address aspects such as clinical trial design and manufacturing processes, and are broadly applicable to many disease applications – not just personalized medicines. They are a positive step that helps streamline pathways for bringing these therapies to patients without compromising regulatory rigor.
Addressing public scepticism
RNA-based therapies were popularized through COVID-19 vaccines, with the technology expanding rapidly in recent years because of its transformative potential. The science itself, however, is not brand new. The attractiveness of this modality lies in speed and scalability: the development of novel mRNA therapies takes just weeks rather than years for traditional therapies. They also come with high efficacy, shown to be over 90 percent in some trials. These attributes facilitate the acceleration of clinical evaluation, with opportunities for personalized medicines, as well as global health responses. There is, however, some unavoidable scepticism that persists surrounding the speed in which the COVID-19 vaccines were developed. This can only be addressed through consistent education that focuses on facts and data, while emphasizing the potential of these treatments, to help overcome fear and false narratives.
The speed with which the COVID-19 vaccines were developed was enabled by decades of research in the foundational science, and the motivation and available funding created by the pandemic. Substantiated data from billions of doses demonstrates that mRNA reduced COVID-19-related deaths significantly, with adverse effects being rare and outweighed by benefits.
Limitations in capacity and a disjointed supply chain – from plasmid through to drug product – mean it can be incredibly challenging to develop RNA therapeutics in the most time-efficient manner. Quite often, it is necessary to use multiple specialist vendors with expertise in drug substance synthesis, drug product development and manufacturing, aseptic fill-finish, and clinical testing. Each organization has their own capacities, priorities, and independent schedules. These can lead to delays in transitioning from one activity to the other.
The pandemic undoubtedly highlighted just how quickly an infectious pathogen can mutate and threaten global health. With vaccines being our primary defence, it is essential to have a range of technologies like these in place for us to respond in a timely manner. The decades of research into mRNA vaccines enabled this when it came to COVID-19, and will continue to enable further innovation in oncology, infectious diseases, and other therapeutic areas.
Another area of intense activity is RNA editing, which has potential advantages over DNA editing due to its relatively transient nature and potential for greater control of gene expression. It will be interesting to see how these develop now some applications are being clinically evaluated, but this does not negate the fact that all vaccines still need to be proven to be safe and effective through preclinical and clinical testing. The speed with which RNA vaccines can be developed compared to historical approaches makes them advantageous as an option for future potential pandemics.
For us, the most exciting of future developments in RNA therapies are those exploring the potential for them to go beyond the development of vaccines for infectious diseases. The speed by which these can be developed has opened up the possibility to develop personalised cancer vaccines to direct the patient’s immune system to the specific proteins expressed in their tumor. Both Moderna and BioNTech have mRNA cancer vaccines in late-stage development, and these could open a new treatment paradigm for a range of cancers and demonstrate the therapeutic utility of RNA technology.
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