Drug development designed to treat rare disease is both a noble cause and a risky business. Rare diseases are typically deadly, debilitating, and devastating for patients and their families, so developing treatments is a vital, if sometimes underappreciated mission.
However, by definition, the market for such treatments is limited, so the business case for a drug developer is often, at best, unclear; without government intervention it would be untenable. Having said that, new technologies and a deeper understanding of the mechanisms of rare diseases is driving investment in the sector.
Patient advocacy groups have played a key role in raising awareness and investment, and are increasingly involved in the design and implementation of clinical trials.
In this article we explore the rare disease landscape, focusing on the emerging and hugely promising technology of ‘gene silencing’. Since around 80% of rare diseases are monogenic, caused by a mutation in a single gene, the ability to stop that mutation from forming toxic proteins is a game-changer.
We will discuss in some detail one form of gene silencing technology, antisense oligonucleotides (ASOs), which is proving to be particularly effective; ASOs are currently being trialled for treating a wide range of conditions, from Alzheimer’s and Parkinson’s to Motor Neurone Disease.
Finally, we speculate on what 2025 might bring for the biotech industry. Will AI advance rare disease diagnosis, drug research and clinical trial design?
Landscape painting
According to the European Commission, there are between 6,000 and 8,000 known rare diseases, with new conditions being discovered regularly.
And according to a report from May 2024 by Global Market Insights (GMI), the market for ASOs was worth $4.4 billion in 2023 and is predicted to grow at a Compound Annual Growth Rate (CAGR) off 18% to reach $19.7 billion in 2032.
GMI cites the increasing prevalence (and diagnosis) of neurodegenerative and genetic disorders, growing investments in research related to gene expression and delivery technologies, and the growth in regulatory approvals for antisense therapeutics as the key drivers behind this growth.
Rare diseases are rare individually but collectively add up to a significant number; up to 400 million people worldwide are affected, and about 90% of those have no current treatment.
But bespoke ASO therapies can be very expensive. For example, a five-year treatment of the ASO drug ‘nusinersen’ costs over $2 million for one patient.
The cost for healthcare systems is also very high; over the last ten years the cost to NHS England of rare disease patients up to the point of a diagnosis was greater than £3.4bn, according to a report from 2018 by Imperial College Health Partners.
Familiar Stories
Getting the right diagnosis, early, is widely agreed to be the most serious challenge faced by those affected by a rare disease. On average, it takes over four years to get an accurate diagnosis, according to Rare Disease UK.
Rare diseases often exhibit a wide variety of symptoms that can overlap with more common conditions, making them difficult to distinguish.
A major challenge in getting the right diagnosis is simply the limited knowledge of rare diseases, especially at primary care level. Clinical knowledge is often lacking, being available only at specialist centres.
The critical problem of a delayed diagnosis is made more acute as the impact of ASOs is greater the earlier they are administered; as time goes on some symptoms may cause irreversible damage. For some the hope may only go as far as delayed progression, though there is some evidence starting to emerge of symptoms being reversed and patients recovering capacities.
For perhaps obvious reasons, the rarer the condition, the less chance of diagnosis and the longer that can take.
Cell out
Messenger RNA (mRNA) is a copy of DNA that leaves the cell nucleus for the ribosomes, where mRNA genetic code is translated into amino acids. These then grow into long chains that fold to form proteins.
ASOs are short, single sequences of nucleotides, designed to bind to mRNA – stopping it from completing its function. It is the ‘sense’ part of mRNA that results in a protein. ASOs are called antisense because they bind to the sense part of mRNA in a complementary manner.
If a gene is known to have a specific mutation that leads to the production of a toxic protein, then the associated mRNA can be targeted by an ASO, leading to a reduction in the volume of toxic protein produced.
‘Gene silencing’ is different from gene editing in that the gene itself in untouched; only its expression as a protein is affected. ASOs are highly targeted and produces much fewer side effects than gene editing.
In trials at University College London Hospitals an ASO is being used to target the mutated gene that results in the Tau protein, one of the two proteins (the other is Amyloid) that are known to be prevalent in patients with Alzheimer’s. The trials have recently been extended after initial success.
Trials are also now underway for gene silencing ASOs that treat Parkinson’s and Motor Neuron Disease. ASOs have shown particular benefits in the treatment of neurodegenerative diseases, including Duchenne muscular dystrophy.
Perhaps most importantly, ASOs target the molecular causes of disease, rather than just treating the symptoms. This is what makes them game-changing.
Patient voice
Patient advocacy groups have historically played a vital role in lobbying for change; in the US in the 1980’s it was advocacy by the National Organization for Rare Disorders (NORD) that resulted in the passage of the Orphan Drug Act (ODA) in 1983, a seminal moment in the history of rare disease drug development.
The ODA included provisions for 7‐year market exclusivity for orphan drugs, tax credits, development grants, fast‐track approval, and the waiving of some fees. These incentives help offset the high costs and risks associated with developing therapies for diseases with small patient populations, making it more feasible for smaller biotech companies to undertake such projects.
In the UK, to take one example, the H-ABC Foundation supports patients and families affected by the disease, advocates on their behalf, and raises money to help fund vital research. They also maintain a map of patients and their specific symptoms, disease progression and more – all vital input to clinical trial design.
Rare disease drug development in 2025
What will this year bring? In a world controlled by economic mantras, rare disease drug development would likely never occur; so government intervention has, in this case, proved vital to the life-chances of millions of patients worldwide.
In 2025, advances in gene therapies will accelerate the pace of drug development; treatments will be developed that are highly targeted and easier to deliver.
But perhaps most encouragingly there is the promise that rapid advances in AI for data analysis, pattern recognition, decision-support systems, genomic analysis, image analysis, and much more, will mean that rare disease identification is much more rapid.
AI tools could help distinguish rare disease symptoms from more common ones, getting to the very heart of the challenge – early identification.
A key factor is learning from real-world data. In a typical consultation, it may be near-impossible to research historical records to look for patterns, tell-tale signs and other data-based clues – precisely what ‘trained’ AI tools can do.
There are issues of course, not least around patient confidentiality and data security. These are paramount in any health system, so the use of powerful algorithms to search vast (real -world) data sets inevitably causes concern.
Ethical and legal issues include questions around accountability; who gets the blame if an AI diagnosis turns out to be wrong?
By Dan Williams, PhD CEO SynaptixBio
About the author
Dan Williams is CEO of SynaptixBio. He has spent over 20 years in the industry after studying at the University of Dundee for a degree in biochemistry and physiology, and a PhD. After his PhD he entered the industry, where he worked his way up to senior scientist. Dan then took over management of a cell research group, initially running a cell biology research and then preclinical development.
Following this he moved to drug development, focusing on the organisation and management of both manufacturing and clinical trials. After that particular therapy went into the clinic and was progressing within clinical trials, he moved to Adaptimmune and switched from biologics to developing cell therapies. He set up the development groups within Adaptimmune, while project managing some of the preclinical research and the move from the partnership with an academic group for their clinical trials, to taking on those clinical trials as a company.
He then managed the larger research group, and moved from that position to the VP of Research Operations. From there, Dan moved to Meatable as the Chief Product Officer. Dan co-founded SynaptixBio Ltd. in 2021 with the aim to push leukodystrophy therapies through to clinical trials.
