How RNA-based therapeutics improve care and benefit patients

RNA-based therapeutics could herald a new era in metabolic care, but how do we ensure patients will actually benefit at scale?
In recent years, advances in the discovery and development of RNA-based therapeutics have been incredible.
The momentum of medicines targeting or harnessing RNA mechanisms has been growing rapidly for approximately five years, when data raised excitement at global medical congresses. However, if you had asked a person on the street, unfortunately few would have been interested. While not unusual, it leaves those with a belief in the potential of this science wanting others to see it too.
The COVID-19 pandemic resulted in monumental changes across the globe, including in this area of medicine. It facilitated the rapid rise of RNA therapeutics in scientific discussion, which became one of the most prominent scientific areas in decades, and arguably is becoming a common term.
The development of RNA-based medicines is a vast field. The first wave of COVID-19 vaccines from Pfizer-BioNTech and Moderna demonstrated how science could quickly develop vaccines with high specificity, without compromising on safety or efficacy. This gives us a glimpse of the therapeutic potential that can be developed when focusing on RNA-based medicines.
Current developments are still only the tip of the iceberg. While vaccines may have stolen the show, the same technology is also showing promise in the prevention and treatment of numerous other diseases. It could even play a role in managing the health of entire populations.
What role might RNAi play in this journey?
One approach within the field of RNA therapy is RNA interference (RNAi) – a process that blocks the production of disease-causing proteins in a highly selective way. RNAi was recognised in 2006 with the Nobel Prize in Physiology or Medicine, and is a rapidly advancing frontier in biology and drug development today. Since then, a number of RNAi therapies have been approved in certain countries across the world, primarily for the treatment of rare diseases.
As RNAi therapies are highly specific to messenger RNA (mRNA) targets, these medicines have the potential to treat any condition caused by the production of a faulty or disease-causing protein. With our understanding of the human genome ever-expanding, and collaboration across industry and research institutes becoming more commonplace, we now have significant opportunities to explore novel approaches to treating some of society’s biggest health challenges.
Unleashing RNAi’s full potential with the UK Biobank
So, the big question now is: ‘What does the future hold for RNA-therapeutics?’ Could they hold the key to treating diseases that affect more than a few thousand individuals ‒ maybe even millions?
A barrier to overcome in order to answer these questions is finding new targets; the root causes of diseases, hidden deep in the genome. In 2018, stakeholders across the industry set out to equip ourselves with that information by entering an agreement with the UK Biobank to form and fund the UK Biobank Exome Sequencing Consortium (UKB-ESC). This funding enabled the sequencing of the exomes (the protein-coding parts of a genome) of half a million UK participants ‒ for whom in-depth medical histories were available ‒ to potentially unravel long-standing health mysteries. Using this information, research has already revealed unparalleled findings and identified new therapeutic targets in areas of unmet need.
From Biobank to breakthrough in metabolic disease
For a while now, evidence has shown a link between patterns of fat distribution and metabolic conditions, including type 2 diabetes, hypertension and heart attack risk. However, there was limited knowledge of the genetic connections between them.
Drawing from the information generated by the Biobank, the human genetics teams leveraged data from over 360,000 individuals, looking specifically at these factors. Through this, they found loss-of-function variants in the INHBE gene that are associated with protection against abdominal obesity and metabolic syndrome. Specifically, these gene variants were found in 1 in 587 individuals who had a lower waist-to-hip ratio adjusted for body mass index (WHRadjBMI), which is a surrogate for abdominal fat, compared to those who did not have these variants. As well as the lower WHRadjBMI, these individuals had decreased triglycerides, increased high-density lipoprotein cholesterol and decreased fasting glucose – all indicating a favourable metabolic profile.
The results of this study have given us fresh insight into the mechanisms that contribute to body fat distribution and its disease sequelae, helping to refine the blueprint for potential therapeutics targeting INHBE. With metabolic syndrome affecting an estimated one in three adults aged 50 or over in the UK, confirming whether targeting INHBE could have a beneficial effect on this condition is extremely important.
This hypothesis is already being tested. Given the INHBE variants result in partial loss of expression of the gene and the expertise we have at Alnylam, we can almost immediately start synthesising drug candidates and testing their potential in in vitro cell models. Ultimately, this means it may be possible to go from identifying potential targets for our therapies to starting clinical trials in drug candidates in as little as 18 months.
The data sequenced by the UK Biobank has been invaluable and something we are continuing to research in the hope of identifying further gene mutations to transform outcomes for people across the world. But the work does not stop there. We are also supporting the Our Future Health research programme, which has the ambitious goal of capturing the genetic and health data of over 5 million adult volunteers across the UK. The goal is to gather a remarkably detailed picture that truly reflects the whole population, offering the potential to unlock transformative discoveries in health, while those whose health information is used in the programme can also benefit from the findings.
Watching the science of RNAi develop has been an eye-opening experience, and the prospect of bringing forward a new technology to modify risk factors in major diseases is hugely exciting. But it has also raised important questions around access, particularly in Health Technology Assessment-based health systems. RNA therapies present the potential to transform long-term health outcomes in major health conditions, but only if they are fully accessible to the patients that need them. This raises questions about how we will be able to reliably predict these long-term outcomes and agree access solutions that are sustainable for both industry and health services.
This will not be without difficulties. Population health is a huge operation, and being able to forecast outcomes for such numbers in the general population will require new approaches as to how we research, assess and pay for medicines. With the ever-changing nature of the world – from population growth to the increased prevalence of preventable diseases – it is important that we adopt a holistic approach and aim to prevent illness and improve health outcomes on a larger scale.
In the last few years, the NHS has pioneered new mechanisms to validate research behind population health, including its first population health agreement (announced in September 2021), aiming to treat up to 300,000 people with high cholesterol. Alongside the goals set out in the NHS Long Term Plan, and the ambitions of the UK Government, MHRA and NICE to expedite patient access to life-changing treatments, the UK has a great opportunity to continue to lead in population health if we continue to collaborate effectively.
Together, we are breaking new boundaries in healthcare and, with the steady emergence of RNA therapies, we are harnessing a revolution in biology for human health. As an industry moving forward in researching and developing medicines for the masses, it will be critical that we continue to engage early and openly, address challenges head-on, and consider that agreements may need to be as innovative as the treatments they encompass.

Paul Nioi, PhD, is Vice-President, Discovery and Translational Research, Alnylam Pharmaceuticals. His work covers new drug target identification and validation, biomarkers and preclinical drug discovery programmes.

Brendan Martin is Senior Vice President, Commercial Innovation Lead, Alnylam Pharmaceuticals. Brendan joined Alnylam in 2016 as one of the company’s first Europe-based employees and has helped to build and establish its presence in the region.