There is no denying that the COVID-19 pandemic has thrust mRNA vaccines into the spotlight, as we have explored in a previous insight. However, the revolution in mRNA-based therapeutics extends far beyond coronavirus vaccines. Here is a sneak preview of what might be next for mRNA...
Vaccines against other pathogens
Long before the COVID-19 pandemic, mRNA vaccines targeting other pathogens were under development, and this trend has only increased. This is not surprising given the advantages that mRNA delivery can offer. A particular strength of mRNA vaccines is their adaptability: the mRNA itself can be swapped with relative ease to make a vaccine against a new target, or to account for mutations in circulating strains of an existing target. This makes mRNA vaccines particularly useful in epidemic or pandemic situations. For example, Moderna, now a household name thanks to their COVID-19 vaccine, are also developing an mRNA vaccine against Zika. mRNA vaccines are also being developed against rabies (CV7202, CureVac), and cytomegalovirus (mRNA-1647, Moderna).
An exciting new development for mRNA delivery is the rise of self-amplifying RNA (saRNA) vaccines. In such vaccines, the incorporated RNA not only encodes the target antigen, but also an enzyme which can replicate the RNA. The benefit of such a vaccine is that the antigen will be expressed over a longer period of time, and the same level of expression can be achieved using a smaller initial dose. Moreover, as many current saRNA candidates are based on alphavirus nucleic acids, receptors in the immune system are able to recognise motifs in the saRNA which activate an innate immune response. This may mean that saRNA vaccines will not require (or will require milder forms of) the extra ingredients, known as adjuvants, that are required in most vaccines to enhance the immune response. Such developments in mRNA vaccine technology may help us to access targets which have previously eluded vaccines, such as HIV-1.
Another potential use of mRNA technology is so-called passive immunisation; this is where the effectors of the immune response, usually antibodies, are administered to the patient rather than stimulating the patient to generate the effectors themselves. Passive immunisation is usually applied therapeutically, after a patient has been exposed to a pathogen, when the patient cannot afford to wait for their own antibodies to be generated, for example in the case of rabies. Direct administration of monoclonal antibodies has also famously been used in the treatment of COVID-19. An mRNA-based approach may enhance this type of treatment. Moderna have developed a candidate mRNA therapeutic (mRNA-1944) which encodes a monoclonal antibody directed against a protein from chikungunya virus, such that antibodies are rapidly produced by the patient after administration of the mRNA. Despite achieving biologically relevant levels of the antibody with an acceptable safety profile in Phase I, Moderna have suggested they will not progress mRNA-1944 to a Phase II clinical trial. Nonetheless, this may pave the way for future developments. It is hoped that mRNA delivery of antibodies may be better tolerated by patients than direct administration of the antibodies themselves.
Vaccines against cancer
While the immune system is primarily thought of as a defence against foreign pathogens, it can also recognise and respond to problems with our own cells. This principle underlies the field of cancer immunotherapy – the harnessing of the immune system to attack cancer. An mRNA cancer vaccine could be used to stimulate an immune response against a tumour by encoding, for example by encoding a "tumour-associated antigen" – an altered form of protein found in tumours. Several such vaccines are under development.
Another approach is the development of "personalised" vaccines specific to an individual patient. Such a vaccine may be designed based on sequencing data obtained from the patient's own tumour. Since tumours continue to mutate (sometimes extremely quickly) it is a significant advantage if the vaccine can be produced and administered as soon as possible after analysis; a task which is more readily achievable with mRNA vaccines than other, more traditional approaches.
Therapeutic applications of mRNA are not limited to vaccines. An example is gene replacement therapy. In short: where a patient's genome encodes a non-functioning form of a protein, a functioning form could be provided by administering mRNA encoding the functional protein.
For example, Translate Bio is developing an mRNA-based treatment (MRT5005) for cystic fibrosis. This disease is caused by a mutation in the cystic fibrosis conductance regulator (CFTR) gene, leading to disruption in the functioning of the CFTR protein in the lungs. MRT5005 encodes a non-mutated copy of this protein that could in principle replace the disrupted protein, but unfortunately the most recent clinical trials did not demonstrate improved lung function. Clearly, as with most therapeutics, additional work will be required to realise the full potential of mRNA-based gene therapy approaches.
A less direct use of gene expression with mRNA is to modulate immune responses by encoding the chemical messengers known as cytokines, or the signalling structures expressed on the surface of immune cells, to stimulate a particular outcome. BioNTech and Sanofi, for example, are evaluating an mRNA formulation encoding the cytokines IL-12sc, IL-15sushi, IFN-α and GM-CSF to promote activation of a cell-mediated anti-tumour response (SAR441000).
With the advantages that mRNA technology can bring, it is not surprising that mRNA-based therapeutics are increasingly popular subjects of research, which of course also means they are increasingly popular targets for patent protection. Moderna alone now have over 100 pending or issued US patents. No doubt others will seek to join them in protecting their mRNA-based inventions.
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