Rare diseases, big advances: how research is powering a new era of treatments

Our knowledge of rare diseases has taken a quantum leap forward in the last few decades, thanks to the revolution in our understanding of genetics since the founding of the Human Genome Project in 1990. It took 13 years to fully sequence the first human genome; the task can now be completed in a matter of hours. As many rare diseases are caused by single gene defects, it is hardly surprising we have made such progress.

But it doesn’t necessarily follow that all new treatments are gene therapies – far from it. Although there have been many exciting developments in gene therapy treatments for rare diseases, gene therapies still face many practical challenges.

However, great headway has also been made in developing other modalities for rare diseases, such as small molecules targeting the gene product proteins and those influencing the messenger RNA. All these approaches have benefited greatly from the advancements that have been made in the genetics underpinning rare diseases.

Understanding disease biology to develop new treatments

As you start to understand which gene(s) are involved in a rare disease, you start to understand the disease biology – and what goes wrong that drives the disease’s pathophysiology. Sadly, many causative genes for rare diseases do not easily lend themselves as tractable drug targets. However, a drug hunter can take that knowledge and search the relevant disease pathways to find suitable points where a drug can intervene in a safe and efficacious way.

Targeting Huntington’s disease

Huntington’s disease (HD) serves as a prime example of a single-gene rare neurodegenerative disease, with therapies in development targeting the gene, RNA, and protein levels. The huntingtin gene responsible for HD was first identified in 1993. Researchers soon discovered that the disease is caused by an abnormal expansion of CAG repeats – a sequence of three DNA ‘letters’ (cytosine, adenine, and guanine) – near the start of the gene. While healthy people have less than 35 of these CAG repeats, if someone inherits 40 or more, they will develop HD at some point in their life. The CAG repeats code for an amino acid called glutamine, and when the polyglutamine chain gets too long it folds incorrectly leading to a toxic gain of function, protein aggregation, cellular dysfunction and ultimately death. In HD the vulnerable cells are neurones in specific areas of the brain. As these neurones die, the symptoms of the disease slowly progress and death follows some 15 to 20 years later. 

This early understanding of the disease pathology meant that, back in the 1990s, people thought we’d very soon come up with treatments. But here we are in 2025, and still no effective disease modifying treatments are available for this terrible progressive condition.

However, there has been enormous progress: not only with gene-based treatments, but also with antisense oligonucleotides (ASOs; which bind to mRNA to stop aberrant huntingtin protein being made), and small molecules which bind to target proteins, all of which are being pursued.

For example, uniQure’s gene therapy AMT-130 is currently in a Phase I/II trial, while Ionis/ Roche’s ASO, tominersen, is being evaluated in a fresh Phase II in a young adult population after mixed results in an earlier Phase III trial. Both aim to lower toxic huntingtin protein and so slow or stop the disease progression.

A new discovery: The role of somatic expansion

However, as is so often the case with complex neurodegenerative diseases, the story is not that simple. What we now know, is that there’s an upstream genetic process that causes the expansion in the CAG repeat sequence in huntingtin – and that is actually the primary driver of disease progression. Toxic huntingtin protein is the subsequent, downstream, toxic process.

There’s now overwhelming evidence that it’s not the CAG repeat that you inherit at conception (typically 40-50 repeats) that actually causes neurodegeneration, but the further expansion of these repeats throughout an individual’s lifetime. This is why HD tends to start becoming symptomatic in middle age, as a long time is needed to accumulate these expansions before neurodegeneration sets in. This process is called somatic expansion.

Genetic studies have shown us that the process that drives this is called DNA mismatch repair, or more specifically aberrant mismatch repair.

LoQus23 is focused on this mismatch repair biology. We’ve picked out a specific target – a protein that forms part of the MutSbeta (MutSβ) complex, which is encoded by the MSH3 gene. MutSβ is involved in DNA mismatch repair but also contributes to the expansion of CAG repeats in Huntington’s disease, making it a promising target for intervention. We are developing allosteric small molecule inhibitors to this protein, thereby arresting mismatch repair and the accumulation of further CAG repeat expansion.

Based on pre-clinical studies, we think it might be possible to delay the onset of symptomatic HD by a decade or two with this approach, or perhaps even longer if therapy is started in younger people, long before they have begun to develop symptoms.

We’ve picked a small molecule approach because they can be administered as oral therapies – a tablet or capsule – which are much more convenient for patients. This convenience is particularly important for people who carry the mutant huntingtin gene but are yet to develop symptoms.

Other biotechs are also working on this disease biology using newer treatment modalities – ASOs and gene therapies. While gene therapies offer a ‘one and done’ treatment, they can be complicated and invasive to administer, and the high one-off cost can prove a barrier to adoption by healthcare providers. Similarly, ASO approaches, which target RNA, require regular treatment with intrathecal infusions, which can be a burden to patients. There’s also the question of safety – if something goes wrong in clinical trials it is easy to discontinue a small molecule, but ASOs, and even more so gene therapies, have very long lasting effects.

The explosion of industrial efforts to find treatments for HD over the last 5-10 years is great news for patients. More and more programmes are reaching clinical trials, which gives us many different opportunities to find safe and effective treatments for this devasting disease. It’s not yet clear which approaches will work best – huntingtin lowering or blocking somatic expansion – but the more ‘shots on goal’ there are, the greater the chances of success. It’s also likely that combinations of treatments may offer even better outcomes for patients than a single treatment alone.

What this means for rare diseases

Huntington’s is just one example where improved understanding of the biology of a rare disease has led to many different therapeutic approaches, but it illustrates many themes which are common to the search for disease-modifying treatments in other rare diseases.

There is still a long way to go. However, our increased understanding of the fundamental biology of rare diseases, and the subsequent flourishing of efforts to develop a wide range of therapeutics for them, offers great hope to the many people around the world living with such conditions.