In August of 2018 the Food and Drug Administration (FDA) approved the first of a potentially game-changing class of drugs called small interfering ribonucleic acid (siRNA). FDA Commissioner Scott Gottlieb, MD announced: “New technologies like RNA inhibitors that alter the genetic drivers of a disease, have the potential to transform medicine so we can better confront and even cure debilitating illnesses.”

This new class of drugs, which is a direct result of the Human Genome project, is unique because the drugs work at the RNA level to specifically silence the production of a disease-causing protein. RNA therapies can be designed to interfere with the production of abnormal proteins throughout the body. Initially focused on infectious diseases and oncology, this technology is now being applied across many therapeutic areas. Whereas DNA technologies – such as gene therapy or gene editing try to fix a dysfunctional gene or re-introduce an intact version of a gene – these new RNA therapies have the ability to utilize a cell’s own internal workings to alter the expression of genes. This gives RNA technology an advantage over DNA technologies because of their wider applications.

RNA technology has the potential to get at the root causes of disease and help bring novel drugs to patients. In this WuXi AppTec Innovator series we will explore the RNA pioneer researchers and companies. STORM Therapeutics is one of the earliest of these trailblazing companies, founded in 2015, as a spinout of University of Cambridge. The company built on the ground-breaking RNA epigenetics work of Professors Tony Kouzarides and Eric Miska for the discovery of first-in-class drugs in oncology and other diseases. It is leading the industry in tackling disease through modulating RNA-modifying enzymes and is developing a unique platform to address these, including RNA methyltransferases. STORM is backed by blue-chip investors Cambridge Innovation Capital, M Ventures, Pfizer Ventures, IP Group and Taiho Ventures LLC.

At the helm of STORM is Keith Blundy, PhD, Director and Chief Executive Officer. Keith joined STORM Therapeutics as CEO in January 2017. Prior to STORM, Keith was Chief Executive of Cancer Research Technology Ltd (CRT), the commercial arm of Cancer Research UK (CRUK), where he drove the development of CRT to become a global leader in the commercialisation of cancer discoveries. He was instrumental in the launch of the £70m Cancer Research Technology Pioneer Fund in partnership with the European Investment Fund (EIF) and BACIT, developed risk sharing drug discovery alliances with AstraZeneca, Teva (formerly Cephalon), Forma, Merck, and MRCT.

WuXi: Do researchers know the full impact/potential of RNA on diseases, or is there much more to learn?

Keith Blundy: No, far from it. The linkage of aberrant RNA function to a number of diseases have only been emerging in the last 5-10 years. In our particular field of RNA modifications, direct linkage and indeed contributions to causality (other than in congenital disorders) have only been described very recently.

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

Keith Blundy: Most of the issues with RNAs as drugs are around targeting to the correct tissue, PK and stability. These provide significant challenges for inherently unstable RNA molecules. This is why alternative approaches like those taken by STORM Therapeutics, to address RNA function through small molecules, which do not have these issues will be attractive. Interestingly, RNA modifications also affect the stability of therapeutic oligonucleotides and there is a potential application for RNA modifying enzyme modulators to assist delivery and efficacy of RNA therapeutics by affecting the modifications on the therapeutic RNA.

WuXi: Will RNA technologies emerge as a dominant treatment modality and if so, how soon?

Keith Blundy: Let me answer by separating RNA as a therapeutic from RNA as a target. Speaking only from this latter viewpoint, clearly, given that all genes are transcribed in to RNA and much of the genome is also transcribed in to RNA, there is great potential in targeting disease through altered RNA function, whether the RNA is a coding or non-coding RNA. It may allow us to address previously non-druggable targets, as well as widening the pool of potential mechanisms to modulate to treat a given disease. Therefore, treatments that affect RNA will become prominent. What remains to be seen is whether the modulatory agents are conventional small molecules or other molecules in the long run, including RNAs.

What RNA-based technology is your company pursuing and what are your disease targets?

Keith Blundy: All RNAs, coding and non-coding are modified post transcriptionally. These modifications are numerous (>100), are enzymatically encoded, often dynamic and affect RNA structure and function (e.g. stability, translation, splicing). Hence if you can establish a strong causal linkage of an RNA to a disease you can in theory effect or correct the function of the RNA by altering its modifications. Making small molecule modulators/inhibitors of the enzymes that make modifications is therefore a new treatment paradigm, and one in which STORM was the first to explore. Our initial focus is in cancer, but we intend to explore other disease areas with our inhibitors.

WuXi: What make your approach compelling and technically achievable?

Keith Blundy: In terms of drugging 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. The first modality although having had some success, suffers from the issues of PK and deliverability mentioned above. Finding direct binders of given RNAs is an exciting new approach, but as of yet with little proof of concept, and it is technically challenging to target the 3D structure of a single RNA in a cell. Storm’s approach of drugging the enzymes, making functionally important modifications, which we have now demonstrated is technically possible, is a less risky approach and one that will progress to proof of concept rapidly.

WuXi: What regulatory challenges do you face? Are they different from DNA-based therapeutics and other types of drugs?

Keith Blundy: The good thing about STORM’s approach is that as we are making conventional small molecule drugs and are on a well-trodden path both developmentally and from a regulatory perspective.

WuXi: What RNA related technologies are you developing that support your small molecule discovery?

Keith Blundy: To understand RNA modifications and their role in a given RNAs function, you must have the means to measure and quantitate the levels of that modification on your given RNA. There is currently no technology widely available to do this – some modifications can be detected by sequencing or immunoprecipitation methods, but these are not comprehensive or quantitative. However, STORM has resolved this challenge 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.

WuXi: Can you please describe the scale and scope of RNA modifications?

Keith Blundy: RNA modifications are universal, playing a role in all types of RNA and its function. Already we have insights into their involvement in cancer, immune responses, CNS diseases and in infection. But as research biology progresses we expect the linkages to other diseases will also become clearer.

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

Keith Blundy: Unlike DNA based therapeutics or possibly even small molecules and antibodies, in theory RNA based therapeutics can address a wide variety of targets (both those perceived as druggable and undruggable) and also with a variety of modulatory effects. For example, to reduce gene expression, to alter splicing, to target both coding and non-coding RNAs that regulate genes directly or epigenetically, to express proteins (as a vaccine) and to correct trinucleotide repeat disorders and even edit the genome. So there is huge potential to treat many types of disease caused by different molecular mechanisms that may otherwise be difficult to address.

At STORM we will add our knowledge of functionally important RNA modifications to the design of such therapies and, in some cases, perhaps be able to complement or even copy the effects of an RNA therapy by modulating the target RNA’s modifications.

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

Keith Blundy: With several RNA targeted therapies now approved and more on the way, we are potentially on the verge of such therapies becoming a mainstream modality. However, for this to happen, there will need to be further improvements in stability (evading the immune system), in PK (lower clearance) and for the delivery to multiple tissues to be solved. The progress made to date with new oligonucleotide chemistries and targeting suggests these issues will be solved and RNA based therapies will become more widely used.