Rare but Resilient:

The Challenges and Hopes of Clinical Research
into Rare Diseases such as Neuroacanthocytosis

 

 

by Amna Ali

for the 2024/25 Student Voice Prize

Introduction

The European Union defines rare diseases as affecting less than five out of 10,000 individuals (1), however the classification of these diseases varies across different countries (2). There isn’t an exact figure for the number of rare diseases worldwide, but this is frequently considered to be between 5,000 to 8,000 (3), with 75% of these having a paediatric onset (4). Whilst individual rare diseases appear to affect only a minority of people,  rare diseases overall affect the same number of individuals as the population of the world’s third largest country; hence, the challenges and unmet needs of individuals with rare diseases are referred to as ‘a human rights and social equity priority’ (5).

This essay explores the challenges, risks and benefits of research into rare diseases, particularly in children and young people. ‘Neuroacanthocytosis’ syndromes, a group of rare neurological diseases, will be referenced within this essay as an example.

Neuroacanthocytosis syndromes

Neuroacanthocytosis syndromes are hereditary genetic disorders defined by a combination of misshaped red blood cells (‘acanthocytes’) as well as progressive decline in neurological function (6). The two main Neuroacanthocytosis syndromes are VPS13A disease (‘chorea-acanthocytosis’) and XK disease (‘McLeod syndrome) (7).

VPS13A disease typically presents in early adulthood, with initial features including obsessive-compulsive behaviours, tics and signs of psychosis (8). The diagnosis of this disease is established by molecular genetic testing, however there is no definitive cure, and it runs a chronic progressive course with many instances of sudden unexplained death or death during seizures (9).

During my interview with Ginger Irvine (10), mother of VPS13A patient Alex (11), I learnt that her daughter’s diagnosis in 1999 took over four years from the first manifestations of the disease at age 24. The only literature on Neuroacanthocytosis were case studies with no research data included. After some fortunate connections steered Ginger’s family towards clinicians who had some awareness about Neuroacanthocytosis, the community grew by finding more clinicians/researchers who had worked in the field of movement disorders. Subsequently, Ginger and her late husband Glenn founded the Advocacy for Neuroacanthocytosis Patients (NA advocacy) to raise awareness and funds for specific research.

Despite sharing many similarities with the former, XK disease typically appears in middle-aged men, with cardiac involvement often being the first feature (12) (13). However, even this can manifest in childhood, as demonstrated by a case report from 2019 detailing a 10-month old Chinese boy presenting with febrile seizures and herpes who was eventually diagnosed with XK disease (12). Laboratory tests showed no acanthocytosis or other haematological abnormalities and there were no significant neurological abnormalities, demonstrating the need for research into the diagnosis of XK disease in children.

Challenges of conducting rare disease research

Companies are often reluctant to invest funds into rare disease research due to a combination of factors including the high costs, risks, and low patient numbers; there are concerns about a scarce market and low investment return (14). In addition to this, the National Institute for Health and Care Excellence has a £20-£30k per quality-adjusted life year (QALY) threshold for cost-effectiveness of interventions (15); such considerations are barriers to incentivising research into rare diseases. NICE appraisals should consider the ‘degree of need and desirability’ when considering innovations rather than only the clinical effectiveness and cost-efficiency (16).

Another obstacle is the very small sample sizes due to the scarce number of individuals with rare diseases who are eligible to participate in research, and the fact that many may not want to do so (17). Furthermore, the limited available participants may not have standardised disease presentations, progressions, and prior treatments and they are likely to be scattered throughout the world (17). The obstacle of a small cohort spread across the world with no standardised database comprising all Neuroacanthocytosis patients has slowed down data collection to support research (10). Additional challenges include the different healthcare systems each NA patient comes from and sometimes even language and culture barriers (10).

There are consistent efforts from the advocacy organisations (NA Advocacy and NA Advocacy USA (10)) to unite and manage patients’ communities across the world. Thanks to their awareness work and funding, some of the post-mortem brain tissue donations led to specific research studies into VPS13A (finished, published in 2023 (18)) and XK (ongoing, started in 2024). However, the process of donation is likely to be obstructed by the challenges listed above.

Additionally, families are often hesitant to enrol children with rare diseases into research, particularly if it is for experimental treatments, due to the perceived risks to physical and psychological wellbeing (19). Researchers may also be offput by the complex and lengthy approval processes, as well as ethical concerns, when conducting experimental trials using young people with rare diseases (19). These considerations are also applicable to Neuroacanthocytosis patients and their families, regardless of pertaining to a slightly different age group (10). There is an extensive approval process for Neuroacanthocytosis disease research, including factors such as whether the individual is dependent on care support, availability of family or support, and whether they are verbal or mobile (10).

 Risks of conducting rare disease research

Clinical trials for rare diseases often involve experimental treatments which can have the risk of causing adverse side effects or having little or no efficacy. This can subject patients with rare diseases and their families to physical and psychological harm, particularly due to the lack of extensive data and understanding of rare diseases (20). Furthermore, there are uncertain long-term effects of new interventions for rare diseases due to scarce previous research and limited data (21).

For families of children and young people with rare diseases, there is a significant financial and emotional strain on them when their loved ones take part in experimental clinical trials. In addition to this, they can be overwhelmed by the associated caregiving requirements, such as travelling, frequent hospital visits, managing side effects, associated with involvement in trials (22). There is also the burden on children’s families to make complex decisions regarding participation in experimental therapies, with potential risks to psychological wellbeing depending on the outcome of the trials (23).

Lastly, there is an argument about the challenge of resource allocation in rare disease research; there is a risk that funding more research into rare diseases, which is often associated with high costs and specialised resources, can put a strain on healthcare resources and limit funding into researching more common conditions which can have ethical considerations (24). However, research into Neuroacanthocytosis could indirectly benefit more common neurological conditions such as Huntington’s disease due to the overlap in symptomology (25).

 Benefits of conducting rare disease research

Clinical trials are often the only way rare disease patients can access experimental therapies with potential to alleviate symptoms or slow the disease progression. Participation in trials can give patients and families a sense of empowerment and hope by contributing to advancing understanding and treatments for their rare disease (26). Where possible, considering joining trials ‘adjacent’ to the specific condition may be an opportunity (10). For example, Alex was part of an early small trial at National Institutes of Health (NIH) on movement disorders, with nine patients being assessed for a week to gather data (10).

There seems to be an increased activity from life sciences companies into developing more N=1 (N-of-one) programs, where research is ‘custom’ designed for a single/very small number of patients to drive the discovery of a relevant treatment. The advocacies, together with the clinicians and researchers collaborating in the Neuroacanthocytosis field, are seeking opportunities to engage with relevant life science companies and drive the discovery of effective therapies (10).

Furthermore, the progress made from research into even one group of rare conditions can have wider disease implications (26). Genetics research into Neuroacanthocytosis syndromes has demonstrated shared molecular mechanisms which may provide broader therapeutic targets that have the potential to benefit multiple conditions, including Huntington’s and Parkinson’s diseases. Therefore, advancing research into Neuroacanthocytosis syndromes can accelerating progress in management of other neurodegenerative conditions (25).

Where do we go from here?

This article aimed to capture the challenges and hopes associated with research into rare diseases, using Neuroacanthocytosis syndromes as an example. Research into these disorders over the past two decades has been driven by generous funding, along with the persistent efforts and collaboration of clinicians, affected families and the dedicated support advocacy organisations.

An avenue to explore is increasing collaboration with adjacent diseases and determining if there is scope in capitalising on existent findings and adjusting them to extend to Neuroacanthocytosis syndromes (10). The NA advocacies are also increasing their collaboration with relevant umbrella organisations for rare diseases that can influence and drive change at a higher level. The resources of a specific rare disease charity are limited, but there is power in the united voices of similar charities, even though the conditions they represent may be different (10).

This article calls to increase support of rare disease research through increased avenues of funding, greater link between researchers and clinicians and continued awareness and fundraising of conditions like Neuroacanthocytosis by dedicated organisations and families (11).

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