Research in rare disease

There are about 7,000 known rare diseases. But only a small percentage of them benefit from targeted therapies. In addition, 6,000 children are born every year with a rare condition that has not yet been described clinically – known as a syndrome without a name. Research is therefore an important beacon of hope for patients, families and clinicians.

Research holds immense importance for the rare disease community. Research into rare conditions helps us understand their natural histories – meaning how they progress over time – which can open up opportunities for:

• more accurate, faster diagnosis;
• the management of symptoms; and
• new treatments.

These advances can all translate into improvements to quality of life for people with a rare condition and their families.

The benefits of research may also extend beyond the realm of rare disease and help us further our understanding of how the human body works. For example, Hutchinson-Gilford progeria syndrome (HGPS, sometimes referred to simply as progeria) is a rare genetic condition that causes features of accelerated aging in children. In 2003, it was discovered that HGPS develops due to a variant in the LMNA gene, which codes for a protein called lamin A.

This protein provides structural support to the nuclei of our cells, but, in HGPS, lamin A is not produced in the typical way, leading to nuclear instability. Thanks to the involvement of those affected by this rare condition, research into HGPS has not only led to better understanding of the condition itself, but has also helped scientists learn more about the biology of aging – knowledge that benefits wider areas of medicine.

The impact of research on families affected by rare disease can be profound, as Xanthe, whose son Jackson lived with a condition called MPS II, knows.

People with MPS II lack an enzyme needed to break down complex sugars, which therefore accumulate in cells, leading to progressive multi-system degeneration. Until 2007, there was no treatment available for MPS II, but collaboration between patients, researchers, families and patient advocacy groups around the world changed that. Patients with this condition can now access enzyme-replacement therapy, which can improve some of the symptoms of MPS II.

Xanthe moved from Melbourne in Australia to Manchester with her late son in order to take part in the clinical trials for MPS II. You can listen to her discuss their experiences on the Rare Disease Podcast: Melbourne to Manchester – a clinical trial story.

Research studies often rely not only on talented researchers but on voluntary contributions from patients and families, and in some cases healthcare professionals. Examples of such studies include Deciphering Developmental Disorders (DDD) and The 100,000 Genomes Project. Since undiagnosed rare conditions are often suspected to be genomic in origin, both of these studies involved the use of modern genome sequencing techniques to try and make new links between genes and disease. One-in-four participants in the 100,000 Genomes Project with a rare disease received a diagnosis for the first time.

Thanks to pioneering projects like those mentioned above, genomic sequencing is now commonplace within the NHS through the national Genomic Medicine Service. This would never have been possible without the collaboration between patients, families, advocacy groups, researchers and healthcare organisations.

Low prevalence

Each rare disease affects only a small number of people – and in some cases only one or two. This can make it difficult to gather important natural history data and to recruit sufficient numbers of participants to clinical trials. To overcome this, participants are sometimes recruited from all over the world (as in the case of Xanthe and Jackson described above), and stages of the drug development process may be combined. Patient advocacy groups are vital to many of these research efforts as they play a crucial role in understanding the needs of patients and in many cases hold a register of people affected by a given condition.

Funding

In the field of rare disease, high research and development costs are compounded by the small market size. Even when treatments are developed, they frequently face funding barriers. High purchasing costs and limited evidence from small clinical trials can prevent approval by assessment bodies. These challenges can be overcome in several ways, including:

• Drug repurposing: Exploring whether existing drugs may be helpful in treating/managing other rare conditions.
• Orphan drug development programmes: Such programmes are often backed by funding from government and/or research charities in response to an urgent health need. They very often focus on rare conditions. An example is NHS England’s Innovative Medicines Fund, which aims to promote early access to promising treatments for patients with a variety of conditions including rare diseases.

Ethics

The majority of rare conditions begin in childhood. Conducting research on children is certainly possible, but comes with additional ethical considerations. You can read more about these ethical considerations in this blog post written by Katie Whitcher, runner up in the Student Voice Prize 2024.

Genomic advancements

As mentioned above, projects like the 100,000 Genomes Project have accelerated progress in rare disease research, with many participants receiving diagnoses or accessing clinical trials as a result of their involvement. The rollout of cutting-edge genomic technology in the NHS means that many more patients and families have access to genomic testing for undiagnosed rare conditions in the form of whole genome sequencing, which offers hope for new diagnoses. Additionally, advances in genomic technology like CRISPR offer the potential to develop personalised therapies for some rare diseases and other conditions in a way that was previously not possible.

It is always important to remember, however, that genomic technologies won’t always yield a result for someone with a rare condition. And advances in genomics will also not help the 20% of people with a non-genomic rare condition.

• Research is an extremely important focus for many families affected by, and clinicians working with, rare conditions.
• Research into rare conditions helps us to better understand biological mechanisms and disease progression, with the ultimate aim of opening up treatment and management options.
• Understanding more about rare conditions can also help us understand more about the pathophysiology of other more common conditions.
• There are specific challenges posed to researchers in the field of rare disease, including low prevalence, ethical considerations and barriers to funding.
• Advances in genomics have opened up more research opportunities than ever before, in turn enabling continuous progress in our understanding of rare diseases. But there is still a long way to go.

For clinicians

• National Institute for Health and Care Research (NIHR): Rare diseases
• Orphanet: Search for a research project
• Rare Disease Research UK

For patients

• Beacon for Rare Diseases: Rare disease research
• Beacon for Rare Diseases: Resource Hub
• CamRARE: Rare Disease Research Network (RDRN)
• NIHR: Be Part of Research