Beyond the vaccines: Messenger RNA’s role in tomorrow’s therapeutics

Whilst the COVID-19 pandemic has provided an unparalleled set of challenges for society, the advent of RNA vaccinations has given us a glimpse of the potential for a brand new class of therapeutics.

Writer: Julian Grinsted
Editor: Anastasiya Kolesnichenko
Artist: Kate Morling

What is messenger ribonucleic acid (mRNA), and why is this curious molecule such a big deal in healthcare? mRNA is an essential intermediary between DNA and protein, allowing the expression of genetic information. Recently, the molecule has proved itself to be an indispensable weapon against the SARS-CoV-2 virus. mRNA COVID-19 vaccines cause cells to make a spike protein from the surface of the coronavirus. This triggers an immune response, meaning that the immune system is able to recognise and destroy the virus if infection occurs. mRNA vaccines hold distinct advantages over conventional vaccine approaches. They are potent, inexpensive and feature exceptionally rapid development. Now, a new class of therapeutic agents based on mRNA are emerging. These therapies function by delivering a message into our cells to produce a specific protein. This protein can have a wide variety of functions, from attacking an infection to supplementing proteins in individuals with rare genetic diseases. 

Adoptive T cell therapy is an extraordinary technique that causes a patient’s own immune system to attack cancerous cells. The practice has not only shown potential in treating glioblastoma multiforme, a brain tumour with a near-absolute mortality rate, but has also been successful in treating metastatic melanoma, a skin cancer that is highly resistant to chemotherapy and radiotherapy, with a median survival rate of under one year.

In 2019, mRNA demonstrated its potential contribution to adoptive T cell therapy. The process involves harvesting T cells from a patient. These are grown outside of the patient, and the mRNA is subsequently delivered into the cells. This mRNA encodes a molecule responsible for detecting antigens and activating the T cells, known as the chimeric antigen receptor (CAR). The T cells later express a version of CAR which specifically recognises the antigens found on the surface of tumour cells. The T cells are delivered back into the patient where they recognise tumour cells and mount a strong response against them. This treatment ensures that the immune system only attacks the tumour and no other tissues. The mRNA will slowly be broken down, meaning that the immune system will gradually return to its original state.

Another potential application of mRNA therapy is the treatment of haemophilia symptoms. Haemophilia A is caused by a lack of blood clotting factor VIII. Haemophilia B is caused by a lack of factor IX. The inherited condition leads to extended periods of bleeding after injury, increased bruising, and joint pain. Males are predominantly affected, with around 1,125,000 men living with the disorder globally. 

Novel mRNA-based therapies are emerging for both haemophilia A and B. mRNA encoding the deficient protein is injected into the patient, where it causes the protein to be produced at therapeutic levels. This supplements the naturally occurring clotting factors and is available in the blood in case clotting is required.

Cystic fibrosis further demonstrates the versatility of mRNA. The genetic condition causes changes to a single protein, the cystic fibrosis transmembrane conductance regulator (CFTR). When functional, this protein regulates the movement of fluids to and from cells. The inactivation of CFTR leads to the accumulation of thick mucus in both the lungs and digestive tract. This is associated with several secondary complications, such as lung infections, osteoporosis, and even diabetes. The condition affects over 70,000 people, with 1,000 cases being diagnosed per year worldwide. 

A new therapy is on the horizon for sufferers of this condition. mRNA can be designed to encode a functional version of CFTR. The therapy could be delivered by a nebulised spray, much like an asthma inhaler. Upon uptake of the mRNA into cells, the functional CFTR will be expressed, reducing the burden of the condition for the sufferer.

So, what is the catch of this incredible technology? Whilst mRNA continues to make dramatic strides in medicine, significant hurdles must be overcome before its potential can be fulfilled. Delivering mRNA into cells is one of the greatest challenges the technology faces. mRNA must be transferred into the cell cytoplasm for translation to occur in the presence of ribosomes. To tackle this problem, mRNA can be placed inside a vector such as a lipid nanoparticle which acts as a delivery vehicle. The vector protects the mRNA from degradation by enzymes known as ribonucleases and can penetrate the cell membrane.

Additionally, mRNA must exist inside cells long enough to be expressed as a protein. Therefore, it must avoid recognition by the patient’s immune system from within cells. Innate sensing mechanisms, which are responsible for an immune response to mRNA, can be avoided by modifying the chemical structure of the nucleotides which are used to build the mRNA molecule.

mRNA vaccines have allowed us to combat the COVID-19 pandemic, with unprecedented rollout speeds. It would be foolish to assume that the technology has peaked when such a variety of applications are emerging in the clinical and preclinical stages. The future seems bright, with mRNA therapeutics reaching fruition. It will be exciting to see how this technology is implemented in treating and preventing disease, particularly in the context of previously untreatable genetic conditions.

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