The science behind gene-silencing technology and the barriers and challenges faced by drug developers

By Dan Williams

'Gene silencing’ is a term used to describe the process of stopping a specific gene from making its associated protein. It is different from ‘gene editing’ in that the gene itself is untouched; only its expression as a protein is affected.

One form of gene-silencing technology, antisense oligonucleotides (ASOs), has proved to be particularly effective, not least because it is highly targeted and produces far fewer side effects than gene editing.

In recent years, the market for ASO-based therapies has grown dramatically, with this growth forecast to continue over the next ten years, according to a number of industry analysts.

This article explains the science behind ASOs and explores the reasons for the predicted growth in the market. It also considers the barriers to that growth and the challenges faced by drug developers, especially as ASOs are seen as a key therapy for many rare diseases.

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- or double-stranded 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, preventing it from producing its associated protein.

If a gene is known to have a specific mutation that leads to the production of a toxic protein, then that specific mutated gene can be targeted by an ASO, leading to a reduction in the volume of toxic protein produced.

In trials at University College London Hospitals (UCLH), an ASO is being used to target the mutated gene that results in the tau protein, which is one of two proteins (the other is amyloid) known to be prevalent in patients with Alzheimer’s. The trials have recently been extended after initial success.

‘Gene silencing is different from ‘gene editing’ in that the gene itself is untouched; only its expression as a protein is affected’

Trials are also now underway for gene silencing ASOs that could treat Parkinson’s and motor neurone disease.

ASOs have shown to have particular benefits in the treatment of neurodegenerative diseases, including Duchenne muscular dystrophy and there are currently four ASO therapies for this condition that are approved by the FDA, demonstrating both effectiveness and market attractiveness.

Perhaps most importantly, ASOs target the molecular causes of disease, rather than just treating the symptoms. This is what makes them potentially game-changing.

ASOs are strong candidates for tackling rare diseases, because around 85% of rare diseases are monogenic – they are caused by mutations in a single gene. If the disease-causing mutation can be identified, then an ASO can be designed that binds to the relevant mRNA.

There are over 7,000 rare diseases, although definitions vary; in the UK and Europe a rare disease is defined as affecting fewer than one in 2,000 people, and in the US it is less than one in 200,000.

The simple, tragic problem is that there is no cure for over 90% of these diseases.
So far, 13 ASOs designed to tackle rare diseases have been approved by the USA Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

But developing ASOs for rare diseases presents several challenges.

It can be many years before a final diagnosis of a rare disease is confirmed and the route to that diagnosis can be highly traumatic for patients and their families – multiple visits to often distant specialist facilities, lack of access to appropriate care and support, and a lack of treatment options are all too common issues.

Healthcare systems are not necessarily designed to quickly identify and react to patients presenting with the typically complex range of symptoms that epitomise rare diseases – and which are often misdiagnosed as more common conditions.

This problem 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 of their condition, although there is some evidence starting to emerge of symptoms being reversed and patients recovering capacities.

For perhaps obvious reasons, the rarer the condition, the lower the chance of diagnosis and the longer that can take.

In addition, bespoke ASO therapies can be very expensive. For example, a five-year treatment of the ASO drug ‘nusinersen’ costs over $2m for one patient.

Finally, not all genetic diseases are good candidates for an ASO-based therapy. Genetic background, disease mechanism, target tissue, delivery route and intervention timing must be taken into account – making the decision far from easy.

These challenges can combine to make ASOs unviable as a treatment option for every patient and sometimes strict eligibility criteria must be applied to choose the patients that could benefit the most.

Taking all of the above into account, ‘the market’ has clearly decided that any obstacles can and will be overcome and that gene silencing will be a major treatment option going forward.

According to a report from May last year by Global Market Insights (GMI), the market for ASOs was worth $4.4bn in 2023 and is predicted to grow at a compound annual growth rate (CAGR) of 18% to reach $19.7bn by 2032.

GMI cites the increasing prevalence 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.

In the last three years alone, there have been over 136,000 applications filed and granted, according to GlobalData’s report Genomics in pharma: anti-sense oligonucleotides. This is strong supporting evidence that the market growth predictions are valid.

Other industry analyses, including Future Market Insights, Grand View Research and Polaris Market Research, also support the predicted rises.

The demand for ASO technology has grown in line with increased work on gene therapy and the drive for ‘personalised medicine’.

In addition, scientists now have a better understanding of how gene expression is regulated, leading directly to the development of ASOs that can target specific (mutated) genes.

Furthermore, there is far more general awareness of neurodegenerative disorders, for which ASOs are well suited, perhaps due to the emergence of an ageing population that experiences more of these types of condition.

Finally, the regulatory system of incentives and approvals has developed to make it viable for both big pharma and smaller biotech companies to invest in finding ASO therapies for rare diseases.

Beyond the scientific, biotech and pharma communities, patient advocacy groups have been effective in campaigning to make the public, medical community and governments aware of the nature and impacts of genetic disorders.

In the UK, the H-ABC Foundation has done a remarkable job in just a few years of raising awareness among the public and medical community of the devastating impacts this disease has on those affected and their families.

The new genetic screening programme announced recently by the UK government is a step in the right direction – it will identify a wide range of conditions, but is limited to those for which there is already a cure available on the NHS, meaning those afflicted with currently untreatable conditions won’t benefit.

The science and technology underpinning genetic treatments is advancing rapidly, to the point where we can identify specific mutations and design drugs that target them directly, stopping the production of toxic proteins. These therapies, if delivered sufficiently early, hold the promise of literally stopping diseases from developing – at the very least, if administered later, they may stop disease progression.

Critically, these gene silencing therapies don’t alter genes themselves, just their ultimate expression as proteins.

They are well-suited to treating a range of neurodegenerative diseases and are particularly relevant for rare diseases, which are predominantly caused by single-gene mutations.

Add to this the fact that ASOs are highly targeted and produce few side effects, and it’s not hard to see why they are increasingly being seen as being right in the vanguard of the next generation of advanced therapeutics.

Dan Williams is CEO at SynaptixBio