World RNA Day: What impact has RNA had on drug discovery?  

Genetic engineering RNA

1 August was first chosen as World RNA Day in 2018 as a play on AUG (adenine, uracil and guanine), a triple sequence of RNA (called a codon) that initiates protein synthesis by the cell. Since then, it has been observed to publicise the importance of this molecule in the generation of proteins in the body. DDW’s Megan Thomas looks at some of the many ways RNA is playing an impactful role in drug discovery.  

RNA Interference (RNAi)  

As defined by the National Library of Medicine (NIH), RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is a conserved biological response to double-stranded RNA that mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes1. The NIH states: “This natural mechanism for sequence-specific gene silencing promises to revolutionise experimental biology and may have important practical applications in functional genomics, therapeutic intervention, agriculture and other areas.” 

There are many examples of ways in which RNAi is impacting drug discovery. In terms of partnerships and development , Orbit Discovery and start-up SanegeneBio have entered into a Master Service Agreement to identify tissue-specific delivery of a wide range of RNA therapeutics, as reported by DDW in January 2023. Dr Neil Butt, Chief Executive Officer of Orbit Discovery, commented: “Sanegene has established an incredible ability to screen for RNAi molecules in a robust and efficient manner. Our aim is to make screening more relevant to the final biological read-outs, to ensure the right leads are selected first time, every time. This has the end goal of enabling the generation of future therapeutics with low toxicity and tissue specificity and ultimately, safer and more effective medicines.” 

In terms of breakthroughs and results, in July 2023, DDW reported that Alnylam Pharmaceuticals has revealed results from its Phase I study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. Also from Alnylam, in September 2022, the European Commission (EC) has granted marketing authorisation for the company’s AMVUTTRA (vutrisiran) for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. At the time of approval, the RNAi therapeutic had been approved in adult patients with stage 1 or stage 2 polyneuropathy, following positive 18-month results from the HELIOS-A Phase III study. 

Antisense Oligonucleotides (ASOs) 

ASOs are a type of nucleotide-based therapeutic that are short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest2. As per a definition provided by AstraZeneca: “Once inside, ASOs bind with high specificity to target mRNA or pre-mRNA, inducing its degradation – effectively silencing it – to prevent its translation into a detrimental protein product. They are a promising approach for the treatment of genetic drivers of disease.”  

AstraZeneca’s non-alcoholic steatohepatitis (or ‘NASH’) study is a prime example of the value of ASOs2. According to the company, a single nucleotide substitution in the PNPLA3 gene results in a mutation that impairs the breakdown of fat in liver cells which raises the risk of NASH. As such, through collaboration with the biotechnology company Ionis Pharmaceuticals and the University of Gothenburg, AstraZeneca are developing an ASO that can target liver cells to ‘silence’ PNPLA3 with the aim of restoring fat break down in the liver. The company said: “Our preclinical research shows promising results that ASO treatment targeted to PNPLA3 reduces fat accumulation in liver cells. Though some genetic mutations are harmful, others can be protective. For instance, a single nucleotide substitution in HSD17B13 has a protective effect against NASH and fatty liver disease (FLD). Together with Ionis Pharmaceuticals, we are investigating how ASOs could mimic the protective effects of the loss-of-function mutation in the HSD17B13 gene.” 

Over at UK biotech firm SynaptixBio, a company which secured £13.2 million to fund its development of the world’s first treatment for TUBB4A-related leukodystrophy, hopes that ASOs, which have previously been used to treat conditions such as Duchenne muscular dystrophy and spinal muscular atrophy, will dramatically improve the quality of, and extend, the lives of TUBB4A patients. As such, the company has entered into a sponsored research agreement with the Children’s Hospital of Philadelphia (CHOP) in the US to develop a TUBB4A-related leukodystrophy treatment from ASOs. Dr Adeline Vanderver, who is programme director of the Leukodystrophy Center at CHOP and a pre-eminent figure in the research related to TUBB4a, said: “ASOs provide the potential to stabilise, improve quality of life, and extend life expectancy of children suffering from the condition. Successful prevention of leukodystrophy progression would be revolutionary, life-saving, and life-enriching.” 

Circular RNAs (circRNAs) 

CircRNAs are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals3, and represent an emerging, powerful mechanism for delivering therapeutics and vaccines due to their protein-coding potential and improved stability in comparison to their linear mRNA counterparts. As reported by DDW, a promising partnership in this field took place in early 2023 between Esperovax and Ginkgo Bioworks, who have partnered to develop circRNAs for a variety of therapeutic applications. By combining omics datasets, computational approaches, and high-throughput screening capabilities, Ginkgo will design, build and screen large numbers of RNA designs that leverage and optimise Esperovax’s novel mechanism of cell-type specific circularisation.

Dr Pirkko Muhonen, Senior Field Application Scientist, Nucleic Acid Therapeutics, at Thermo Fisher Scientific, shared what’s next for RNA-based medicine post-pandemic with DDW. On the topic of circRNAs, she said: “Research into circRNA is moving quickly, as scientists work to understand the role these elusive molecules play in normal cell function and in pathogenic disease. Recent research findings suggest circRNA molecules could be used as biomarkers of disease, drug targets, or even therapies or vaccines for prevention or treatment of infectious diseases and cancer.  

“One approach to using circRNA as a therapeutic molecule is to target disease-associated endogenous circRNA and mitigate its activity through the use of an RNAi therapeutic. Another potential clinical pathway is to use engineered exogenous circRNAs to produce therapeutic proteins within target cells. circRNA has also been used to upregulate advantageous endogenous circRNA expression in both cultured cells and animal models. circRNA can also produce large quantities of protein for a longer duration than linear mRNAs, making these molecules a potential alternative to mRNA or saRNA for the stable expression of a therapeutic protein or antigen.” 

Messenger RNA (mRNA) 

As defined by the National Human Genome Research Institute, mRNA is a type of single-stranded RNA involved in protein synthesis, made from a DNA template during the process of transcription4. In drug discovery, its potential has skyrocketed following its use in a number of Covid-19 vaccines, with Pfizer’s Covid-19 vaccine becoming the first mRNA product to achieve full FDA approval in the US6 

The metaphorical drug discovery floodgate which opened thereafter includes Moderna’s exploration of an mRNA HIV vaccine, and in June 2022, the company announced the planned establishment of an mRNA Innovation and Technology Centre that will develop mRNA vaccines for respiratory diseases, including Covid-19 vaccines, that can protect against multiple variants. As reported by DDW, the aim for the centre is to help future-proof the UK against emerging health threats and the first mRNA vaccine is expected to be produced in the UK in 2025. Harwell, a science and innovation campus in Oxfordshire, was selected for the location.  

There are many more examples of where mRNA has been successfully used in drug discovery, including a clinical trial of an experimental universal influenza vaccine developed by researchers at the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center (VRC), which begun enrolling volunteers at Duke University in Durham, North Carolina, in May 2023. This Phase I trial will test the experimental vaccine, known as H1ssF-3928 mRNA-LNP, for safety and its ability to induce an immune response. Meanwhile, a research effort by researchers at the University of Queensland to develop an mRNA vaccine against Group A Streptococcus (Strep A) has begun after securing almost $8 million in funding by the Leducq Foundation. 

For more on the topic of mRNA, DDW has several resources which expand on the multifaceted and continuously growing topic. In June 2023, DDW’s Diana Spencer took a closer look at three companies hoping to be the first to bring new mRNA therapeutics to the market. Moreover, DDW has produced a webinar, Where are the breakthroughs in mRNA drug discovery and development? as well as an in-depth report on uses for this exciting technology, and an eBook titled Riding the mRNA highway: development, manufacturing, and beyond.   



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