RNA – in the midst of a medical revolution

Ribonucleic acid (RNA) therapies are promising to change the way we treat diseases. From cancer therapies to vaccines and treatments for genetic diseases, the opportunities are almost infinite.

Ribonucleic acid (RNA) therapies are promising to change the way we treat diseases. From cancer therapies to vaccines and treatments for genetic diseases, the opportunities are almost infinite.

The importance of RNA has historically been focused on the most well-known form, with the molecule regarded as a simple “carrier” of the genetic code between DNA and ribosomes, the sites of protein translation. While this is the role of one type of RNA, termed ‘messenger’ RNA (mRNA), countless other varieties exist, fulfilling diverse functions and roles within the nucleus and in the cytoplasm. RNAs can roughly be divided into so-called coding and non-coding RNA and have been revealed as integral to most major biological processes, but also to be involved in human disease. Lately, mRNA-based vaccines have made furore, preventing COVID-19 cases and severe disease triggered by SARS-CoV-2. There is promise that the concept can be applied to many other prophylactic vaccines but also potentially to therapeutic approaches. The last decade has seen an RNA revolution and the true potential of the molecule is only just being realised.

A journey of discovery

RNA is a molecule made up of similar units (nucleotides) to that of DNA. Individual nucleic acids link to one another in chains, each attached to bases which convey information in a form of code. Unlike DNA, RNA exists in a diverse set of forms, performing unique functions including switching genes on and off, editing other RNAs and transporting amino acids to build proteins. The molecule was first discovered in 1961 [1], following decades of work by scientists across the world trying to decipher the secrets of cellular replication. Despite the initial discovery of mRNA in the 1960s, it took until the 1990s for any demonstration of RNA use as a therapy.

Two ground-breaking studies in this decade shaped the way that we view RNA today, pre-empting therapies including the vaccines produced by BioNTech/Pfizer and Moderna which have been given to millions of people to protect against COVID-19 [2]. Firstly, a group showed that injecting mRNA into cells could cause the cells to produce the protein encoded by the sequence [3]. It was subsequently shown that introducing mRNA encoding proteins not recognised by the host would lead to an immune response [4]. This principle was a highly valuable contribution eventually leading to vaccine production. [5]

A third study in 1998 showed that an alternative form of RNA, termed small interfering or ‘siRNA’, could affect cells differently to mRNA, blocking normal protein production instead of triggering it [6]. This study led to a Nobel Prize for the authors and the development of two forms of siRNA treatment: antisense oligonucleotides (ASO) and RNA interference (RNAi). RNA silencing is a conserved biological response to double-stranded RNA molecules which regulates gene expression. ASO and RNAi are short sequences of RNA capable to specifically bind to a target sequence and to block normal protein production. The potential of these molecules was applied to treat diseases such as a devastating neurodegenerative condition known as hereditary transthyretin amyloidosis (ATTR). The disease involves build-up of mutant protein in multiple organs, leading to premature death for those that carry the gene. The novel double-stranded RNAi treatment Onpattro® (active substance patisiran) revolutionised treatment and became the first RNAi-based therapy to gain FDA approval in 2018. It was shortly followed by the single-stranded ASO treatment Tegsedi® (active substance inotersen). Both drugs are able to prevent the accumulation of the harmful protein by blocking its production and therefore alleviating symptoms and prolonging life for patients.

RNA saves the day – easing the burden of the COVID-19 pandemic

While the potential of RNA in vaccines had already been recognised in the early 1990s, it has taken decades and multiple collaborations of research groups across the world to make those ideas a reality. Although RNA is a simple molecule, it is highly prone to degradation and thus complicated to manufacture. Many lost faith in the concept, until the pioneering couple of Özlem Türeci and Uğur Şahin launched their company BioNTech with the Austrian immunologist Christoph Huber in 2008 [7]. This would spark the creation of the vaccines that have helped ease the burden of the COVID-19 pandemic today. The vaccines work using tiny fat droplets to help deliver and keep the mRNA molecules stable.

RNA typically comes as a single-stranded biopolymer which includes self-complementary sequences. Molecules can further be modified in numerous different ways forming highly complex structures. In order to use siRNA used as a therapeutic approach, structural modifications are crucial to stabilize the molecule and to prevent it from destruction. One such modified form used in RNA silencing is a class of short RNAs which are processed from double-stranded precursor by the enzyme Dicer. These micro-RNAs (miRNAs) have also shown great potential in therapies.

RNA and precision medicine – a future for cancer treatment?

The pandemic has catapulted RNA technology into the spotlight, accelerating efforts to deploy the technology in other diseases such as chronic HIV infection [8] and even cancer. Various approaches are being used to treat cancers including both mRNA vaccines against cancer associated proteins and siRNA silencing cancer genes. The siRNA approach was demonstrated to prevent cancer growth in a 2010 clinical trial [9]. Promising results were also revealed with APN401 (APEIRON Biologics, now invIOs) [10], a novel cellular therapy utilizing autologous peripheral blood mononuclear cells (PBMCs) from patients with various solid tumors. PBMCs, which are known to contain various immune cell types involved in anti-tumor activity, are electroporated ex vivo thus allowing a specific siRNA targeting the novel checkpoint of immunity, Cbl-b, to enter the cells. Based on first promising results in clinical trials, Cbl-b silencing by siRNA technology may give rise to therapeutic approaches for all kinds of tumors. The next years will reveal how RNA technology will shape the future of personalized medicine.