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Messenger of DNA, Therapeutics and Coronavirus: How are they all linked?

This blog was written by Ashley Chin, BSc, a PhD candidate in the Division of Experimental Medicine at McGill University and Montreal Clinical Research Institute. Her research areas of interest include RNA and cell biology.

The answer lies in RNA. As we may know from the central dogma of molecular biology, RNA is best known as a messenger for DNA. Genetic information is passed on from DNA, to messenger RNA (mRNA), to protein. However, this dogma has led to an overly simplistic view. In the last few decades, scientists have dedicated themselves toward understanding the role that RNA molecules may play beyond being a simple genetic blueprint. They realize that having proper control over these microscopic regulators can translate into macroscopic health benefits in animals, including human. As such, the search for innovative RNA-based therapeutics have set sail. 

An Emerging Drug for Mankind

For many years, RNAs have been deemed to be easily degraded and too cumbersome to be manipulated in the laboratory. Any scientists working with RNA would agree with this. This is because the human body is constantly releasing RNases into the environment, enzymes that are used for degrading RNA during normal cellular maintenance and for protecting us against harmful microorganisms. Although this benefit may initially seem like an advantage to you, it has in fact prevented scientists from using RNA as a potential therapeutic for many years, until some recent breakthroughs.

In recent years, RNAs are being explored as a new class of pharmaceutical target and drug, especially as vaccines for neurological disorders and infectious diseases (1-3). For example, to treat children with a crippling neurodegenerative disease called spinal muscular atrophy, building upon the initial RNA research conducted by Adrian Krainer and C. Frank Bennett, who were co-recipients of the 2019 Breakthrough Prize in Life Sciences, one pharmaceutical company and biotech teamed up to harness the power of antisense oligonucleotide therapy, a novel technique whereby carefully modified versions of DNAs are introduced into the cells (1-3). This is achieved by injecting the modified molecules into the fluid surround the spinal cord as a way to alter mRNA splicing, an editing process that is crucial for maintaining genetic information in the cells (1, 3). Additionally, last year, in a study conducted by Feldman and colleagues, they successfully produced effective mRNA vaccines against the influenza A viruses, the mastermind behind seasonal flu every winter. The researchers specifically targeted the H10N8 and H7N9 influenza strains that surfaced in 2013 by producing vaccines that contained chemically modified, full-length forms of those virus mRNAs. The vaccines were given in the deltoid muscle surrounding the shoulder during phase 1 of the clinical trial and yielded promising immune response from healthy participants (4).

What about the pandemic that is currently taking the world by storm – paralyzing our daily routines, sinking the global economy and killing countless lives? In fact, much like the mRNA vaccine mentioned above, scientists are working at unprecedented pace to explore the feasibility of using mRNA vaccines to combat SARS-CoV-2, the coronavirus that is causing COVID-19 (5). This is because the traditional form of vaccines we are used to, which usually works by introducing a weakened or dead form of the virus to the body, requires a lengthy manufacturing time. Take the typical seasonal flu shots, an egg-based vaccine, as a more recent example, the virus needs to be first injected into a fertilized chicken’s eggs, where the selected virus strains incubate and replicate. Following, the viral containing fluids need to be harvested and deactivated before the purified virus antigen can be used in a vaccine (6). With the clock ticking and infection spreading as we speak, any mean to shorten vaccine manufacturing time is lifesaving.

RNA scientists believe mRNA vaccine can be a suitable solution in a time pressed pandemic as the mRNAs can serve as instruction molecules to direct a person’s immune system to make their own protein reserve to combat a viral invasion. In this sense, the recipient uses the immune cells within its own body as a manufacturing hub for antibodies, rather than relying on external manufacturing capabilities, which is expected to save time when compared to traditional way of manufacturing vaccines.

In fact, albeit a development in progress, mRNA vaccines have other key advantages over traditional vaccines or DNA-based vaccine. The first and foremost is safety. mRNA is non-infectious, so it will not be integrated into the recipient’s genome and it can be digested by normal cellular processes. Through various chemical modifications, the longevity of these mRNAs in the body can be controlled. Additionally, the efficiency of mRNA delivery can be increased through designing and packaging the mRNA into protective, carrier molecules, which would enhance stability and encourage rapid uptake by the cells (7). Furthermore, mRNA vaccine can not only be a rapid alternative, but it is also scalable, as it relies on in vitro transcriptions, chemical reactions that are commonly practiced in laboratories, rather than relying on external factors such as the availability of hen’s eggs in addition to laboratory manipulation (6, 7).

As such, a large mRNA-based biotech is evaluating mRNA-1273 as a putative candidate vaccine for the novel coronavirus (5). The concept surrounding its vaccine is to inject a portion of mRNA that codes for the spike-like protein that is located on the surface of the virus, which allows it to bind to and invade human cells. In this fashion, the synthetic mRNA can travel throughout the bodies of their recipients, stimulating their immune systems to produce beneficial antibodies against the spike protein. Thus, when someone is exposed to the virus, the antibodies will be able to stop an infection by coating spike protein on the virus surface and preventing its capacity to attach to cells. Phase 1 clinical trial consisted of 8 healthy participants and yielded a positive outlook in terms of safety and efficacy. Phase 2, involving a few hundred healthy participants, is currently underway. If all goes well, phase 3 is scheduled to commence in the coming weeks (8).

Similarly, using mRNA-based technology, a pharmaceutical giant has teamed up with another biotech to develop a coronavirus vaccine (5). The most promising vaccine candidate is named mRNA-BNT162b1. This mRNA codes for a receptor binding domain antigen that is found on SARS-CoV-2, a portion of the protein that is required for the virus to bind to human cell. These companies have started phase 1/2 of their clinical trial, which consists of 45 healthy participants. Although some minor but not serious adverse effects were observed, the vaccine generated neutralizing antibodies that are predicted to prevent the coronavirus from operating. In fact, following two administrations of the low doses tested, the concentration of these antibodies were 1.8-2.8 times when compared to recovered patients (9). Nevertheless, whether higher concentration equates to immunity against the coronavirus remains to be tested (9, 10). Phase 2b/3 of the clinical trial is expected to start in few weeks (9).

At this point, due to the inherent complexity of our biological systems and the development of an effective vaccine, only time will tell whether we can effectively fight RNA with RNA. Afterall, this novel coronavirus is an RNA virus and it would be interesting to see if we can give it a taste of its own medicine – by using synthetic mRNA molecule to create protein that our own immune systems can learn to combat. This is an exciting era for RNA researchers, as the world anxiously awaits its good news.

Although we have only discussed mRNA vaccines in the context of COVID-19, around the world, there are many other types of vaccine being explored in parallel. With the urgency of this matter, we certainly do not want to put all our eggs in one basket and concurrent vaccine development using a diversity of approaches are warranted.

Perspectives

We are only beginning to understand the many roles that RNAs play in our world. With the rapid technological advances, RNA-based therapies hold great promise for improving modern medicine within the foreseeable future, but much work remains to be done before it can establish itself as an efficient, scalable and go-to clinical solution. It may potentially serve as a great alternative or replacement for gene therapy against certain diseases. This is especially true since mRNA will not integrate into the host genome, minimizing the risk of unpredictable outcome associated with gene therapy.

References

1. Mercuri, E., et al. (2018). Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med, 378, 625-635.

2. Garde, D. (2018). Researchers behind Biogen’s breakthrough drug win big at ‘Oscars of science’. Statnews. https://www.statnews.com/2018/10/17/researchers-behind-biogens-breakthrough-drug-win-big-at-oscars-of-science/

3. Bennett, C., Krainer, A., & Cleveland, D.W. (2019). Antisense oligonucleotide therapies for neurodegenerative diseases. Annual Review of Neuroscience, 42, 385-406.

4. Feldman, R.A., et al. (2019). mRNA vaccines against H10N8 and N7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine, 37, 3326-3334.

5. Servick, K. (2020). Meet the company that has just begun testing a coronavirus vaccine in the United States. Sciencemag. https://www.sciencemag.org/news/2017/02/mysterious-2-billion-biotech-revealing-secrets-behind-its-new-drugs-and-vaccines

6. Yeung, J. (2020). The US keeps millions of chickens in secret farms to make flu vaccines. But their eggsw on’t work for coronavirus. CNN Health. https://www.cnn.com/2020/03/27/health/chicken-egg-flu-vaccine-intl-hnk-scli/index.html

7. Pardi, N., et al. (2018). mRNA vaccines – a new era in vaccinology. Nature Reviews, 17, 261-279.

8. Grady, D. (2020). Moderna coronavirus vaccine trial shows promising early results. The New York Times. https://www.nytimes.com/2020/05/18/health/coronavirus-vaccine-moderna.html

9. Pfizer and BioNTect. (2020). Pfizer and BioNTect announce early positive data from an ongoing phase ½ study of mRNA-based vaccine candidate against SARS-COV-2. Pfizer News. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-early-positive-data-ongoing-0

10. Herper, M. (2020). Covid-19 vaccine from Pfizer and BioNTect shows positive results. CNBC Newsletters. https://www.cnbc.com/2020/07/01/coronavirus-vaccine-from-pfizer-and-biontech-shows-positive-results-report-says.html

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