When Margaret Keenan, a 90-year-old woman from Coventry (UK), received the first COVID-19 vaccine, it was just 11 months after the discovery of the virus that caused it and less than 9 months after a pandemic had been declared. It was the 8th of December 2020 and biomedicine was setting an all-time record. By comparison, it took 5 years to develop and approve the Ebola vaccine and 7 years for measles. This unprecedented speed was made possible by a combination of factors, including exceptional funding and global cooperation, but one of these factors made all the difference: RNA technology.

Far from being a one-off solution, this breakthrough has opened the door to a new generation of therapies based on RNA (a key molecule in essential processes such as protein synthesis) that are revolutionising medicine by offering more versatile, precise and personalised ways to fight disease. 

“RNA-based vaccines are just the first step in a revolution. In the near future we’ll see not only new vaccines but also drugs that, using a similar technology, will correct or improve different diseases” explains Puri Fortes, a CaixaResearch researcher at CIMA, University of Navarra, who specialises in new RNA-based therapies to treat liver cancer.

The potential is huge but so are the challenges, such as making the RNA more stable in the body, minimising adverse effects, aiming it precisely at the affected tissues and perfecting the delivery systems. 

Together with five researchers from the CaixaResearch network, we examine how this new generation of therapies, the fruit of decades of silent research, could usher in faster, more precise and more personalised medicine.

Beyond vaccines

RNA (ribonucleic acid) is a close relative of DNA and exists in several forms. The best known is messenger RNA (mRNA), which copies genetic instructions from DNA and transports them to ribosomes, where proteins are made that are essential for life. This “messenger” function has been key to the development of COVID-19 vaccines but its applications go much further. 

The group of Pascual Torres and Manuel Portero, CaixaResearch researchers at the Institut de Recerca Biomèdica de Lleida (IRBLleida-UdL), is exploring its potential to treat amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disease. “In ALS, certain types of mRNA are altered, generating erroneous instructions that end up producing defective proteins” explains Manuel Portero.

Manuel Portero, CaixaResearch researcher at the Institut de Recerca Biomèdica de Lleida (IRBLleida-UdL).

Their therapy aims to neutralise one of the defective RNAs involved in ALS by using a technique known as antisense RNA, consisting of a small RNA sequence that is perfectly paired, like a piece from a jigsaw, with the anomalous RNA. “By binding to this RNA, it prevents it from accumulating and being used by the cell to make erroneous proteins, thereby interrupting the progression of cell damage” adds Pascual Torres.

Their research project is also studying the possibility of using these abnormal RNAs as biomarkers of the disease, i.e. as biological signals to help detect it and monitor its development. “This would help us to develop highly precise therapies, even personalised for each patient, and is one of the most promising advantages of RNA-based therapy” says Portero.

The immune system as an ally

RNA is also revolutionising cancer treatment, especially by means of immunotherapies and anti-tumour vaccines. The team of Toni Celià-Terrassa, a CaixaResearch researcher at the Hospital del Mar Medical Research Institute (IMIM) in Barcelona, is working on new mRNA-based therapies that help our own immune system to detect breast cancer more effectively. “Our goal is to increase the number of patients who can benefit from immunotherapy” explains Celià-Terrassa. “We also have other lines of research which seek to design treatments that prevent the generation of metastasis, blocking the mechanisms used to evade our immune system in metastatic organs” he notes.

Toni Celià-Terrassa, a CaixaResearch researcher at the Hospital del Mar Medical Research Institute (IMIM).

Even so, the field of immunotherapy still faces numerous challenges, starting with understanding the complexity of the immune system at an individual level. The CaixaResearch Institute, the first research centre to specialise in immunology in Spain and one of the first in Europe, will play a decisive role in this area. “The pioneering approach of the CaixaResearch Institute is fundamental because immunology is involved in most chronic pathologies, as well as ageing and its associated diseases. Advances in immunology can be applied across many different areas of health. For instance, we employ this multidisciplinary approach in our studies on tumour immunology since the same mechanisms could also be significant in infectious, autoimmune or neuroimmune diseases” explains Celià-Terrassa.

New instructions against cancer 

Apart from mRNA, there are other types of RNA that also have enormous therapeutic potential. This is the case of non-coding RNAs which aren’t involved in the manufacture of proteins but do play a role in regulating a range of cellular processes. Many of these RNAs are present in tumour cells and can make the difference between a benign and a malignant tumour. The team of Puri Fortes, a CaixaResearch researcher at the Centre for Applied Medical Research (CIMA), University of Navarra, is studying one of them: an RNA called NIHCOLE, which is key in the development of hepatocarcinoma, one of the most aggressive forms of liver cancer.

Puri Fortes, a CaixaResearch researcher at the Centre for Applied Medical Research (CIMA), University of Navarra.

“NIHCOLE is our favourite non-coding RNA” explains Fortes. “It’s not found in healthy tissue but it does appear in the tumours of most patients with hepatocarcinoma. If you apply radiotherapy or chemotherapy to these tumours, you break their DNA but the tumours survive thanks to NIHCOLE, which acts as a powerful tool for repair” explains Puri Fortes. For this reason, her aim is clear: “We want to attack NIHCOLE to deactivate the mechanisms that enable the tumour to repair its DNA. If it can’t be repaired, the tumour cell can’t survive”.

In addition to the liver, NIHCOLE RNA has also been identified in other types of cancer, such as breast, lung, colon and head and neck cancers. “The potential of these therapies is huge. We need to discover more RNAs like this one, to determine their sequences, understand how they fold into a cellular structure and what function they have. Then we’ll be able to reverse the path and obtain thousands of possible therapies, much more efficiently and simply” says Fortes.

Precision strategies for liver diseases

Some of the non-coding RNAs with the greatest therapeutic potential are small interfering RNA (siRNA) or antisense RNA, capable of silencing specific genes. Although their use in cancer therapies is being widely investigated, they might also have great potential for rare diseases. The team of Malu Martínez-Chantar, principal investigator of the Liver Disease laboratory at CIC bioGUNE, which is supported by CaixaImpulse Innovation, is studying how to apply this technology to block a gene involved in cell metabolism. The overexpression of this gene, i.e. the excessive production of its protein, has been linked to several rare liver diseases.

Malu Martínez-Chantar, principal investigator of the Liver Disease laboratory at CIC bioGUNE.

“So far, we’ve observed remarkable therapeutic efficacy in different models of liver disease: from metabolic disorders to alcoholic liver disease, paracetamol-induced toxicity and certain types of cancer such as cholangiocarcinoma” explains Martínez-Chantar. “We believe this strategy has great potential in the treatment of a range of liver diseases, both inflammatory and oncological”.

The secret lies in targeting highly specific molecular pathways. “These diseases share molecular pathways that contribute to chronic inflammation, oxidative stress and excessive remodelling of liver tissue” adds Malu. “Being able to selectively block these processes with siRNA offers a highly effective and less toxic alternative to many conventional treatments”.

A new starting point

The five CaixaResearch researchers agree: RNA is a watershed in the medicine of the future. “It’s entirely feasible that, in a few years’ time, RNA therapies for diseases such as liver disease will be as common as conventional drugs” says Malu. “They can be designed much faster and more flexibly, enabling them to be tailored to individual patients and to new molecular targets with greater precision”.

Puri Fortes suggests an even more disruptive possibility. “It will enable us to create personalised vaccines against cancer, designed from the RNA sequences of each tumour . Although tumours share the same genome as healthy cells, there are some proteins that only appear in tumour cells. Once these proteins have been duly identified, the rest of the technology to develop vaccines already exists. All that remains is to go through the process we’ve all learned thanks to COVID-19, i.e. produce a PCR to detect them, create an RNA that encodes them, introduce it into a nanoparticle… and vaccinate the patient”.

For years RNA had remained in the background but it’s now at the forefront of a new era in medicine. An era that promises smarter, more personalised and effective therapies for some of the most complex diseases we face.