Research Field Cell & molecular biology

In the RNA

In August 2018, the FDA approved the first of a potentially game-changing class of drugs - small interfering ribonucleic acids (siRNAs). In a press statement announcing the approval of Onpattro (Patisiran), FDA Commissioner Scott Gottlieb announced, “New technologies like RNA inhibitors that alter the genetic drivers of disease have the potential to transform medicine so we can better confront and even cure debilitating illnesses (1).”

This new class of drugs are unique because they work at the RNA level to specifically silence the production of disease-causing proteins. Whilst initial research has found application in oncology and infectious disease, the technology is now being more broadly applied across a broader range of therapeutic areas.

DNA technologies including gene therapy or gene editing attempt to fix a dysfunctional gene or re-introduce an intact version of a gene. In contrast, RNA based approaches utilize a cell’s own internal machinery to alter the expression of genes. This broader range of applications gives RNA technology a significant advantage over DNA technologies.

RNA technologies have the potential to target the root causes of disease and help bring more novel drugs to patients. WuXi Xpress spoke with pioneering researchers and companies in the field as part of its Innovation that Matters series (2). Here, we summarise their discussions…

The Experts

Keith Bundy, Director and Chief Executive Officer at STORM Therapeutics

Founded in 2015, STORM is a spinout from the University of Cambridge, UK. Applying advances in our understanding of the role of RNAs in epigenetics, the company is working on first-in-class drugs in oncology and other diseases.

Roel Schaapveld is Chief Executive Officer at InteRNA

InterRNA focuses on applying RNA therapeutics to cancer treatment. Based in the Netherlands, the company is using its proprietary microRNA platform to develop candidates that target key processes in cancer initiation and progression.

Robert Habib is Chief Executive Officer at MiNA

MiNA deploys a systematic approach, translating saRNA based therapeutics from bench-to-bedside. This has culminated in a clinical trial in its first two years. The company focuses on cancer and other diseases.

What benefits do RNA-based therapeutics offer that you wouldn’t find with DNA-based approaches?

Roel Schaapveld: RNA-based therapeutics function by modulating the internal machinery of our own cells, resulting in changes to the expression of certain genes. This opens up a wide range of potential therapeutic applications and provides a higher degree of flexibility in approach, allowing researchers to address previously untreatable targets. The field comprises a variety of different approaches that either result in the up- or down-regulation of certain proteins in a cell. Depending on the application, this process can be targeted to a very specific protein or towards a broader range of proteins.

In contrast, gene therapies or gene editing technologies, such as CRISPR, commonly referred to as DNA-based therapies, have a rather different objective. The aim is to repair a dysfunctional gene or reintroduce an intact version to produce a functional protein. These approaches are, at least for the time being, fairly limited to rare disease modalities – the risk of permanently altering the human genome remains too high for more widespread use.

RNA therapeutics promise a larger variety of applications, but due to  challenges in stability and delivery, have taken longer to reach patients. However, over the last few years, we have seen a significant uptick in development as the technology has advanced and novel solutions for these challenges have been identified. This is exemplified by the FDA/EMA’s approvals of certain antisense and siRNA therapeutics. RNA-based therapeutics now represent a new drug class, standing alongside small molecules and antibodies as emergent technologies.

Robert Habib: One of the major benefits of RNA-based therapeutics is that by engaging with a cell’s own manufacturing machinery, we are able to modulate proteins in diseases that cannot be targeted with conventional medicines. Being able to influence a much larger number of biological pathways will provide radically new ways to treat patients.

RNA-based therapeutics are comprised of several different classes, each engaging various components of a cell’s manufacturing machinery through distinct mechanisms of action. In that sense, it is important to consider RNA-based therapeutics as a battery of novel modalities rather than just one. As well as small activating RNAs (saRNAs), used to upregulate the transcription of a specific gene, there are a number of alternative approaches. These include antisense oligonucleotides, exon skipping oligonucleotides, RNA interference (RNAi), aptamers, microRNA mimetics and antimirs, immunomodulatory CpG, mRNAs and a variety of other technologies. This broad range of RNA therapeutics offers a more flexible approach to address a variety of diseases. Initially, DNA-based approaches were favored in drug development, in part due to inadequate delivery technologies for the less stable RNAs. However, over the last ten years, the field has seen major advances in both delivery technologies and manufacturing capabilities.

What are the leading RNA technologies and what diseases do they target?

RS: The market is currently dominated by RNA interference technology and mRNA technologies. Numerous companies have demonstrated their interest in these approaches because they have shown considerable therapeutic potential – particularly for chronic diseases such as cancer, diabetes, AIDS, tuberculosis, and certain cardiovascular conditions.

Research and development has so far concentrated efforts on infectious diseases and oncology due to their high global prevalence and unmet medical need. Both RNAi- and mRNA-based approaches are currently being explored. The goal? To stimulate the immune system to fight a specific target structure. In contrast to the more historically utilized RNAi based approaches, microRNAs can be used to address a variety of targets within a specific and/or across several disease-associated pathways with a single therapeutic. In multi gene diseases such as cancer this is key - it offers the potential for a combination treatment in one drug.

Approval of an RNA-based therapeutic in a patient population as large as cardiovascular disease could be the next milestone for the supply chain...

RH: I don’t believe that you can necessarily rank RNA technologies - they all have their applications and merits. Having said that, antisense oligonucleotides are at a very mature stage of development. They’ve seen considerable clinical and commercial success, with application in CNS, oncology, and cardio metabolic diseases.

We were all very excited when the first RNAi medicine was approved in 2018 (3). mRNA therapeutics have garnered tremendous attention over the past few years, largely because of the technology's flexibility in modulating such a large range of proteins. However, using mRNA technology for therapeutic intervention is not trivial and the pioneers are appropriately digging in the trenches for the long-term.

What scientific advances are needed to make RNA technologies more effective medicines?

Keith Bundy: Most of the issues with RNAs in terms of their efficacy involve ensuring the correct tissue is targeted. There are also concern about their pharmacokinetic properties and stability. Inherently unstable RNA molecules will, by nature, provide these considerable challenges. This is why alternative approaches to address RNA function using small molecules, which do not have these issues, are proving particularly attractive. The research community is continuing to learn more about how RNA modifications affect the stability of therapeutic oligonucleotides. With that has come the realization that there is potential application for RNA modifying enzyme modulators to assist delivery and efficacy of RNA therapeutics by affecting the modifications on the therapeutic RNA.

RH: The underlying challenge for many RNA-based therapeutics remains efficient delivery to a target cell. RNA-based therapeutics inherently have few drug-like properties, which means they have a hard time getting inside cells in the body. Huge strides have been made to enable the effective delivery of RNA-based therapeutics, but the reality is we are only at the tip of the iceberg. Some RNA-based therapeutics will also require breakthroughs in manufacturing technology in order to be a realistic proposition in general medicine

Will RNA technologies ever emerge as a dominant treatment modality?

KB: To answer that question necessitates separating RNA as a therapeutic from RNA as a target. Given that all genes are transcribed into RNA and much of the genome is transcribed into RNA, there is great potential in targeting disease through altered RNA function, whether that be coding or non-coding RNA. These approaches may allow us to address previously non-druggable targets, as well as widening the pool of potential mechanisms of treatment for a given disease. Therefore, treatments that affect key properties of RNAs will become prominent. What remains to be seen is what form modulatory agents will take in the long run.

RS: Although it is difficult to say what the future holds for RNA technologies. The approach has already gained significant attention, especially in recent years with the market approvals of Spinraza (antisense) and Onpattro (siRNA). More companies are harnessing the potential of RNAs to tackle diseases where current treatment options fail to deliver durable responses.

RH: What matters most is finding ways for all these various RNA modalities to deliver superior outcomes for patients poorly served by today's conventional medicines. To emerge as a dominant treatment modality alongside small molecules and antibodies will require delivering these outcomes to a very large number of patients – and only certain RNA technologies are suited to have that kind of impact. For example, certain technologies can only modulate proteins that are relevant to genetic diseases affecting relatively small numbers of patients. Other technologies may require quirks of chemistry that limits their breadth of use due to safety, route of administration, or manufacturing costs

What RNA-based technology are you pursuing?

KB: All RNAs, coding and non-coding, are modified post transcriptionally. These modifications are numerous, often enzymatically encoded, and affect RNA structure and function (e.g. stability, translation, splicing). If you can establish strong causal linkage between RNA behavior and disease, you can, in theory, effect or correct the function of the RNA by altering its modifications. Making small molecule modulators or inhibitors of the enzymes that induce modifications is a potential new method of treating certain diseases. This is the area we are working in. Our initial focus is on cancer, but we intend to explore other disease areas too.

To understand RNA modifications and their role in RNA function, we must also have the means to measure and quantitate their levels. There is currently no technology widely available that allows this. Some modifications can be detected by sequencing or immunoprecipitation methods, but these are not comprehensive or quantitative. We have developing unbiased proprietary mass spectrometry methods to detect and quantitate RNA modifications in a sequence specific manner. This allows us to accurately determine the effects of our small molecule inhibitors on the target RNA as part of understanding its therapeutic effect.

To drug RNA, one can think of using RNAs themselves (e.g. RNAi, antisense) and small molecules that bind directly to the RNA to affect its function. Using RNAs themselves results in a number of pharmacokinetic and delivery issues, some of which we’ve  mentioned earlier. Small molecule RNA binders are another exciting avenue. However with little proof of concept this remains technically challenging..

RS:InteRNA develops sophisticated microRNA drug candidates to create effective monotherapies for various cancer types. Our lead candidate, INT-1B3, has shown powerful immune system activation, tumor regression and pronounced long term immunity based on a CD8+ T cell immune response. The safety profile and pronounced anti-tumor efficacy demonstrated in preclinical studies makes INT-1B3 stand out as a promising alternative where current combinatorial strategies with anti-PD1/PD-L1 fail. Our goal is to enter the clinic with this lead candidate later this year in liver cancer and triple negative breast cancer. In parallel, we will also continue to advance our pipeline of microRNA drug candidates for other oncology indications based on our differentiated functional screening platform.

Our near-term milestones for 2019 include the completion of GLP tox studies and entry into the clinic with our lead candidate, INT-1B3, with the objective of testing it in solid tumors. Achieving these milestones will be an important step for the corporate development of InteRNA and will give us the opportunity to further explore the promising potential of our unique microRNA approach.

RH: We are pioneering a new class of medicines called saRNAs (small activating RNAs). saRNAs share many features with other RNA therapies but work through an entirely distinct mechanism called RNA activation. saRNAs can upregulate intracellular or secreted proteins for therapeutic benefit and have been shown to increase protein levels for both naturally expressed and epigenetically silenced targets. By working at the gene level, saRNA-based medicines are able to restore components of cellular machinery, such as powerful transcription factors that are currently considered “undruggable” by conventional medicines. The beauty of saRNA is also that well-established oligonucleotide designs can be used as triggers for gain of function. That allows MiNA to leverage years of pharmaceutical development, from assays to delivery, which have enabled a robust pipeline in short order.

We are currently focused on three therapeutic areas: immuno-oncology, metabolic diseases, and genetic diseases. Our lead candidate, MTL-CEBPA, is currently in Phase 1b development in patients with advanced liver cancer. Pre-clinical and early clinical testing suggests that MTL-CEBPA may enhance the efficacy of a range of cancer therapies - principally by modulating the tumour microenvironment. We have been very encouraged by the early clinical results and plan to initiate further clinical trials for MTL-CEBPA in the future. Together with Boehringer Ingelheim, we are also working on a set of undisclosed targets to treat NASH and liver fibrosis.

By the end of 2019 we hope to initiate a new clinical trial, evaluating MTL-CEBPA in combination with checkpoint inhibition in a range of solid tumor malignancies. In early 2020 we look forward to presenting the results of our Phase 1b study of MTL-CEBPA in combination with sorafenib in patients with advanced liver cancer.

What kinds of manufacturing challenges do you face?

RS: Fortunately, our high level of experience in the field of RNA biology, and the fact that we have been working on the technology since 2008, has resulted in a steady improvement of our platform and manufacturing capabilities through our qualified CMOs. In doing so, we’ve already addressed a lot of the current drawbacks. We’ve significantly improved the stability of our lead microRNA candidate and optimized the delivery strategy towards specific tissues.

RH: As saRNAs are short oligonucleotide sequences, they can be manufactured using methods advanced by antisense and RNAi, such as solid phase synthesis and purification by chromatography. A number of contract manufacturers around the world have optimized and harmonized these methods to establish platforms that rapidly scale to commercialization. Additionally, thanks to economies of scale, the suppliers of the amidite raw materials have been able to offer successively lower prices, making RNA-based therapies an economically feasible proposition in diseases affecting growing numbers of patients. Approval of an RNA-based therapeutic in a patient population as large as cardiovascular disease could be the next milestone for the supply chain.

To emerge as a dominant treatment modality alongside small molecules and antibodies will require delivering these outcomes to a very large number of patients – and only certain RNA technologies are suited to have that kind of impact...

Considering the wide variety of treatment modalities, where would you rank RNA-based technologies in importance?

RS: For a long time, cancer therapeutics has been viewed through a “one fits all” principle, but survival and remission rates are still poor for many cancer types. Advances in screening technologies have shown that no two individual tumors share the same mutational landscape – a property that is key to their ability to develop resistance and evade the immune system. Targeting several hallmarks of disease simultaneously, will be key to fighting heterogeneous and fast adapting diseases like cancer and influenza, respectively. RNA therapeutics could offer a competitive advantage.

RH: Researchers around the world are consistently pushing the limits of small molecules and biologics. Emergent modalities including cell and gene therapies are making their cases known. However, the flexibility to modulate a vast range of target biology, with chemically manufactured drugs and with tuneable duration of action, sets RNA-based therapeutics apart as a drug class with extraordinary potential.

After two decades of research, the first RNAi therapeutic was approved in 2018. How do you think this class of medicines will evolve over the next five years?

KB: Several RNA targeted therapies are now approved, and more are on the way. We could be on the verge of such therapies becoming a mainstream modality. However, for this to happen, there needs to be further improvements in stability (evading the immune system) and pharmacokinetics (lower clearance). The challenge of delivering to multiple tissues must also be overcome. Progress to date with new oligonucleotide chemistries and targeting suggests these issues will be solved and RNA based therapies will become more widely adopted.

RS: The last couple of years have been a turbulent time for RNA-based technologies. Due to collective hype and optimism – particular surrounding microRNA technologies - many companies pushed their products into the clinic prematurely. This has caused major setbacks for the field, despite the immense potential of the technology. Consensus has moved towards a greater appreciation of the necessity of a therapeutic approach that addresses multiple components of a pathway rather than knocking out single genes.

RH: We are already seeing a significant uptake in RNA therapies entering the clinic. Personally, I predict that drug discovery for the most mature modalities will begin to uncouple from the pioneers and be distributed globally. Academic labs, new biotech ventures and pharmaceutical generalists will join together to unlock the fullest potential for RNA-based therapeutics. In my mind, that would be the ultimate affirmation of RNA-based therapeutics.

This roundtable has been compiled by The Medicine Maker using interviews from the WuXi Xpress Innovation that Matters series

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  1. FDA, “FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease”, (2018). Available at: Accessed June 27, 2019.
  2. WuXi AppTex, “WuXi Xpress”. Available at Last accessed June 26, 2019.
  3. D Adams et al., “Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis”, N Engl J Med, 379, 11-21 (2018). PMID: 29972753.
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