Game-changing mRNAs

The potential of mRNAs can be effectively harnessed to target genetically unique cancer cells

Game-changing mRNAs

Apart from a lot of misery and pain, the COVID-19 pandemic has given us a lot of insights into the treatment of other diseases like cancers.

All wars are known to leave behind devastated cities, buildings, mass graves and feelings of grief, and the war on COVID-19 has also destroyed human lives and economies. Many believe that life will never be the same again and the fear of pandemics will constantly haunt us in the future. In spite of all such losses, this war has also led to a technological breakthrough that will make life better in the long run.

Research on using mRNA as a therapeutic molecule in cancers and autoimmune diseases has been ongoing for more than a decade, but the true extent of its utility has been seen only during the current pandemic. This medical revolution, involving the use of mRNA therapeutics which encodes the antigen of the infectious agent, has been made in a very short span of time in comparison to conventional vaccines. Most vaccines are made from viruses grown in chicken eggs or mammalian cells in large amounts and are deactivated before delivery. However, synthetic mRNA is very simple and easy to manufacture and is injected into the body where they enter the cells to produce antigens. The cells then present these antigens to the immune system to prepare it for a fight in case of any future infections. From now on, as soon as the virus genome is sequenced, the mRNA can be synthesized and given as therapy or vaccine. However, the major challenge for mRNA vaccines and therapies is delivery. Still, there are several delivery mechanisms being identified and more are in development.

Shift in course

Early vaccine research on COVID-19 involved engineering the spike-protein gene into the adenovirus that causes the common cold in chimpanzees but is relatively harmless to humans. Scientists at Oxford University developing a vaccine for Middle East Respiratory Syndrome (MERS) used this approach. Bill Gates Foundation collaborated with this team of scientists to take it to clinical trials, but the vaccine did not live up to expectations. Johnson & Johnson used a similar vaccine approach of using a human adenovirus to carry part of the spike-gene. However, it too would not work in humans who are already exposed to adenovirus. It is in this context that scientists explored another method to transfer genetic material into human cells without the use of viral vectors — by using DNA or RNA directly. DNA vaccines have been tested by a few companies such as Inovio Pharmaceuticals, involving the use of DNA carrying instructions to produce the spike-protein or its parts to train the immune system to react to the real virus. The primary challenge was the delivery of the DNA into human cells and the need to transport it into the nucleus to start producing the spike protein. It would need a lot of DNA to be injected into a patient’s arm to cause minute amounts of DNA to get into the cell’s nucleus and the approach was not considered efficient.

This led the researchers to think about using RNA, which does not need to be transported into the cell’s nucleus to translate itself into a protein. Scientists such as Sydney Brenner and James Watson first identified and isolated RNA in 1961. However, it was hard to use RNA as a vaccine as the body’s immune system often destroyed mRNA when it was engineered and introduced into the body. It was as recently as 2005 that new scientific breakthroughs were made in the form of synthetic mRNA molecules that can be delivered into human cells using lipids without having to be destroyed. When the pandemic struck, companies like BioNTech and Moderna — which were not working on such infections — took it as a challenge to develop a new RNA vaccine by combining RNA with lipid carriers. Pfizer, which was working on developing a vaccine for flu using mRNA technology, partnered with BioNTech to start work on COVID-19.

Similarly, Moderna — which never set out to work on developing vaccines for a pandemic — was supported by funding from the US government to leverage its expertise in the area of developing lipid nanoparticles for delivery of mRNA to come up with a vaccine for COVID-19. By November 2020, both companies had vaccines in late-stage clinical trials with more than 90% success. It wasn’t long before US FDA gave emergency use authorization to start producing and supplying these vaccines.

The messenger RNA has the power to transform modern medicine by stimulating or training our immune system to fight infections. Both BioNTech and Moderna are also pioneers in cancer research and are developing immunotherapy using mRNA to help the body’s immune system to identify and kill cancer cells. mRNA’s ability to be reprogrammed means that it may be possible to engineer them as treatments for several intractable diseases like cystic fibrosis, cancer and HIV. Cancer cells, in particular, create unique proteins, and mRNA can be used to precisely target these genetically unique tumour cells and train the immune system to eliminate them. In fact, before the pandemic, Moderna was working on developing therapies for autoimmune diseases such as multiple sclerosis. In short, the current pandemic — with its wave of destruction — has also inaugurated a new era of mRNA therapies and vaccines.

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