Messenger RNA, the key to personalised medicine

How long have scientists been studying messenger RNA (mRNA)? What were the major stages of the research?

Palma Rocchi: Since the discovery of mRNA in 1961 by Jacques Monod, François Jacob and André Lwoff at the Pasteur Institute, which earned them the Nobel Prize in 1965, a whole field of medical applications has opened up around two approaches: vaccination and the targeting of mRNA for therapeutic purposes. The story of mRNA vaccines begins thirty years ago with research from the likes of Jon A. Wolff in 1990 at the University of Wisconsin or Frédéric Martinon and Pierre Meulien in 1993 at the Pasteur Institute. At the time, vaccine development strategy had come up against certain limiting factors: the stability of the mRNA, its delivery, its immunogenic effects and its production in large quantities. It was the development of innovative solutions over the past fifteen years, and in particular the work of Katalin Karikó and Drew Weissman, at the University of Pennsylvania, which paved the way for mRNA vaccines against COVID-19. Extensive research conducted over three decades in oncology, concerning prototype mRNA vaccines specifically targeting cancer cells has also been very important. It was this know-how and the insights gathered that have contributed to the speed of production of vaccines against COVID-19.
 

When did the story start for Moderna?

Sandra Fournier: As early as 2011, Stéphane Bancel, the CEO of the company (created in 2010 in Cambridge in the United States), bet big on mRNA technology. For ten years, the start-up invested 2.5 billion dollars in research, thanks to fundraising. During this period, Moderna did not launch any commercial products or generate income, so it was a genuinely risky undertaking. But the expertise acquired by its 800 researchers put it in a position to offer a vaccine in record time when the COVID-19 pandemic struck in early 2020. Once the SARS-CoV-2 virus sequencing was available, it took only 48 hours to determine and synthesise the mRNA strand, 42 days to produce the first batch of vaccine candidates for clinical trials and nine months to prepare for clinical trials before obtaining marketing authorisation, issued by the European Medicines Agency on January 6, 2021. It was certainly a scientific feat but also an industrial one because the company had to raise another billion dollars to build its first production plant and then produce and deliver 807 million doses of vaccines worldwide in 2021.

Does the simplicity of production and the speed that you have just illustrated with the example of the vaccine against COVID-19 explain the success of mRNA?

S.F.: Stéphane Bancel compares our platform, responsible for mRNA production, to a smartphone. With more than 4,000 employees today, the company has grown the number of candidate vaccines and therapeutic solutions from 20 to 48 in only three years. These candidate vaccines and treatments are like smartphone applications — they can be updated very quickly. This technology allows for great agility. In the case of COVID-19, we can constantly adapt to the emergence of new variants of SARS-CoV-2. This involves modifying the sequence of the mRNA coding for the vaccine antigen, and then producing the appropriate vaccines on an industrial scale all over the world. We have just signed four framework agreements to set up production plants in Canada, the United Kingdom, Australia and Kenya.

P.R.: COVID-19 has raised awareness of the potential of mRNA technology to very quickly produce a vaccine or a drug candidate with very high specificity, compared to about ten years with a conventional molecular approach. The example of Milasen, a drug created in 2019 at Boston Hospital by Dr. Yu’s team for Mila, a young girl suffering from a neurodegenerative disease, illustrates this perfectly. The sequencing of her genome allowed us to identify the mutation at the origin of her disease and to produce a molecule (an antisense oligonucleotide) specifically targeting this mutation. This molecule attained market authorisation in less than a year! This very particular example of a medicine tailor-made for a single person is unique at the present time, but it perfectly illustrates the possibilities offered by mRNA therapies.

You are working on the development of antisense oligonucleotides (OAS) in oncology, a field where research on the use of mRNA is booming. What are the advantages of this approach?

P.R.: As I mentioned, mRNA technology has been studied for a long time by cancer researchers, with the aim of developing not only vaccines but also drugs. Around the world, since the early 2000s, several teams like ours have been working on the development of therapeutic molecules, OAS, which will target mRNAs coding for proteins involved in tumour growth. This research opens the way to real personalised medicine: by specifically targeting genetic mutations, it makes individualised treatment possible. In the laboratory, our team is exploring this strategy against hormone-resistant prostate cancer. We demonstrated the influence of the Hsp27 protein, over-expressed in tumour cells, in resistance to treatments and developed an OAS that targets the corresponding mRNA. The first clinical results are encouraging! Our ambition is to produce OAS cocktails. These nano-medicines would be veritable Swiss Army knives for inhibiting the expression of several mRNAs and thus “bypass” the cancer, in combination with more conventional treatments, such as chemotherapy, hormone therapy, radiotherapy or immunotherapy.
 

Does the mRNA vaccine show any promise for anti-tumour treatment?

S.F.: Moderna is working in this direction, with the development of therapeutic anti-cancer vaccines, which do not aim to prevent the disease, like those intended for prophylaxis, but to cure it. This is the case for the mRNA vaccine candidate for the treatment of melanomas with a high risk of recurrence, which we are currently developing with the pharmaceutical group Merck. Phase IIb clinical trial results announced at the end of 2022 are very encouraging. By combining this personalised vaccine with KEYTRUDA®, an immunotherapy treatment produced by Merck, the risk of recurrence or death is reduced by 44% compared to conventional treatment alone. The principle of this vaccine is to activate the immune system: the mRNA will modify the behaviour of certain immune cells to force them to reject the tumour. It is a personalised vaccine, designed according to the characteristics of the tumour of each patient, which is studied from a biopsy. Phase III of these trials should be launched this year. If we succeed in developing this vaccine, there literally will be as many treatments as there are patients. And we want to extend this approach to other types of tumours.