Antisense oligonucleotides: new therapies for n = 1 rare diseases

We need new treatment options for rare diseases. Around 3.5 million people in the UK have a rare condition and 95% of these cases do not have effective treatments. This is largely because clinical information to diagnose and treat individual rare diseases is lacking, as these diseases affect a very small number of patients.

Some of these diseases are so rare that only a single case (n = 1) or a few cases (n = few) are known globally. Therefore, rare disease patients need highly individualised treatments.

What are antisense oligonucleotide therapies?

Antisense oligonucleotides (ASOs) are short, single, or double-stranded nucleotide sequences designed to bind to a specific RNA. They can be used to reduce the expression levels of the target RNA, which lowers the levels of a disease-associated protein. ASOs can also be used to alter how the RNA is processed, which can alter the protein structure and restore its function to normal levels. 

Around 85% of rare diseases are monogenic – arising from mutations in a single gene. Knowing the underlying disease-causing mutation allows the production of specific ASOs that can bind to the target RNA. Therefore, ASOs can be used to develop individualised treatments that may address the root cause of a rare disease, including for n = 1 cases. 

To date, 13 ASO therapies have received approval from the USA Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for different rare diseases. In the UK and Europe, several facilities have also been created to accelerate production of antisense oligonucleotide therapies for rare disease patients, including for n = 1 cases, such as the Nucleic Acid Therapy Accelerator (NATA), the Rare Therapies Launch Pad, the Dutch Centre for RNA Therapeutics, the European Collaboration 1 Mutation 1 Medicine (1M1M), and the N = 1 collaborative.

But developing antisense oligonucleotides for rare diseases is a challenge

The challenges of developing ASO therapies for rare disease patients were discussed at two symposiums I recently attended – the inaugural symposium for the UK Platform of Nucleic Acid Therapy and the Genomics England Research Summit.

Few rare diseases get diagnosed, and it is common for diagnosis to take about five years. The rarer the condition, the less chance of diagnosis and the longer it can take. Without a diagnosis, the disease-causing mutation and how it functions within the disease cannot be identified, and a suitable antisense oligonucleotide therapy cannot be developed. Even when a mutation is identified, a suitable ASO therapy can only be developed for the ‘right’ kind of mutation – mutations that cause abnormal RNA expression or processing. 

Developing bespoke ASO therapies is time-consuming and expensive. For example, a five-year treatment of the ASO drug ‘nusinersen’ costs about $2.25 million for one patient. 

Managing patient expectations is necessary

Current challenges in developing antisense oligonucleotide therapies prevent them from being offered as first-line treatment options to all patients. Instead, eligibility criteria are used to select patients that stand to benefit the most from ASO therapies. Researchers at the Genomics England Research Summit identified patients as more likely to be considered for ASO therapies if:

• Their rare disease is in a ‘high diagnostic yield’ group, for example, a patient with neurological disorder has a higher chance of getting diagnosed because there are more patients with this disease or a lot of research work is happening on the disease.
• They have a diagnosis, and the disease-causing mutation and its mechanism of action is known.
• The disease-causing mutation is amenable to ASOs.
• The patient has gone through the usual care pathway and is stable enough to receive treatment for the next few years. 

ASO-based therapies are most beneficial when offered as early as possible because, as the disease progresses, certain symptoms can cause irreversible damage. However, current delays in rare disease diagnosis and producing suitable ASOs mean early treatment may not be possible for all. For such patients, instead of a cure, ASOs may offer other clinical benefits such as delayed disease progression. It is important to communicate the limitations of ASO-based therapies to patients to help manage their expectations.

The rare disease journey affects parents and caregivers too

At the UK Platform of Nucleic Acid Therapy symposium, parents shared their common experiences of the rare disease journey

• Without a clear diagnosis for their child, parents are often left without clear actionable steps. 
• Parents turn to online forums, where other parents of rare disease patients provide support or even help diagnose their child.
• Parents may not have the necessary background to understand scientific jargons related to their child’s disease, which they learn to better communicate with researchers and clinicians.
• Parents champion foundations to raise awareness about a particular rare disease and funds to treat it.
• Parents become ‘experts’ on their child’s rare condition.

As a result, parents and caregivers often develop a high risk tolerance towards a new rare disease treatment that may not have undergone the usual, extensive clinical validity assessment. Therefore, bespoke ASO treatments are seen favourably.

Moving forwards: collaboration is key

The rarity of rare diseases means that data, knowledge, and expertise on individual conditions is siloed in geographical pockets. Speakers at the UK Platform of Nucleic Acid Therapy symposium emphasised that collaboration between academia, industry, clinicians, and regulatory bodies is crucial for knowledge sharing and to enable large-scale analysis of rare disease data. Engaging with parents and caregivers is also necessary, as they bring real-life experience to the table. They can help define what clinical benefit means for different rare disease patients which can help influence key clinical and regulatory decisions around ASO drug recommendations.

To ensure better care can be provided to rare disease patients, work on the following needs to continue:

• Better and faster diagnosis for rare diseases relying on whole genome sequencing instead of exome sequencing, where necessary, to identify disease-causing variants.
• Easy-to-access databases that are constantly updated with globally curated information on rare diseases and details of these conditions.
• CRISPR-based screens that offer the possibility of simultaneous identification of multiple gene targets for rare disease therapy.
• Incentives to develop and market antisense oligonucleotide therapies for n = 1 rare disease cases, for example, by allowing ASO facilities to have exclusive manufacturing rights to an ASO drug over a ten-year period.
• Faster approval process for antisense oligonucleotide therapies developed for very rare conditions. Because of the small number of rare disease patients affected, there may not be enough clinical evidence to support the use of an ASO drug. Regulatory bodies such as NICE have simplified their criteria for the treatment of rare diseases. 
• Better clinical guidance and signposting to relevant rare disease resources for patients, parents, and caregivers.

While antisense oligonucleotide therapies offer significant hope for treating rare diseases, including for n = 1 cases, it is important to keep in mind the associated challenges and limitations as we move forward with patient treatment.