Accelerating therapy development, application, and evaluation for individuals with rare genetic diseases

“Individually rare, together common” requires an innovative approach

While treatments are increasingly being identified for rare diseases, they often do not reach

the patient, illustrated by the fact that in 95% of all rare diseases there is yet no licensed

treatment. A disease is considered rare when it occurs in less than 2000 individuals

(according to European guidelines), although collectively, these diseases are quite common,

affecting approximately 7% of the population.

Legislation generally requires that therapies for rare diseases are tested and licensed

according to the same rules established for common diseases. However, conventional

methods for evaluating treatment effectiveness are hampered by the small patient

populations. Single-case experimental designs (SCEDs), including n-of-1 trials, offer a

solution. These designs offer benefits that are also applicable to common diseases, such as

individualized treatment options and the generation of high level of evidence on treatment

effectiveness (due to the use of within-subject randomization). Treatment response varies

across different types of diseases, regardless of rarity. Whereas conventional methods often

assess treatment effectiveness based on the average effects among responders and non-

responders, SCEDs take into account both within- and between-subject heterogeneity.

Moreover, the individualized approach implies relevance of treatment responses and

outcomes for patients.

From preclinical to clinical therapies

At the Emma Center for Personalized Medicine (ECPM), we accelerate the development,

application, and evaluation of therapies for individuals with rare genetic diseases through a

tailored approach. Established in 2022 at the Amsterdam University Medical Center (the

Netherlands), the ECPM aims to innovate and speed up diagnostics, personalized therapies,

and care for those with unmet medical needs (Van Eeghen et al., 2022) . Our multidisciplinary

team of (pre)clinical researchers and physicians facilitates the rapid translation of new

knowledge and technology into personalized care (figure 1).

Figure 1. Therapy-accelerating wheel of the Emma Center for Personalized Medicine.

©Health2media.

The ECPM Therapy Clinic serves as a hub for conducting SCEDs, optimizing

(targeted) therapy selection, and generating evidence of treatment effectiveness. We employ

the ‘indicating-performing-monitoring’ triad to tailor the right therapeutic strategy for the right

person at the right time, based on their unique phenotypes and genotypes. This triad

addresses: 1) identifying the best possible therapy, based on evidence of target mechanism

and therapy (cellular, animal model, clinical), pathophysiology, patient characteristics and the

clinical need; 2) selecting an appropriate study design, considering the desired level of

evidence, patient burden, pharmacovigilance, and suitable comparators; and 3) defining

relevant endpoints, including type, relevance, validity, and responsiveness of outcome

measures, frequency of measurements, interim analyses, and data collection.

With our growing, multidisciplinary expertise, we support physicians by providing

template protocols, knowledge, skills, and resources for SCED studies, in consultation with

authorities for market approval and reimbursement. We also conduct multiple SCEDs in both

clinical and research settings, testing various (repurposed) drugs and (genetic) therapies for

different diseases (den Hollander et al., 2023; Müller et al., 2021, 2024) .

As SCEDs can sometimes place additional burden on participants, such as the use of

placebo or treatment withdrawal, we occasionally allow patients to choose the type of SCED

they prefer. It is essential to clearly explain the advantages and disadvantages of different

SCED options, including the expected level of evidence for treatment effectiveness and any

potential burden associated with the trial.

Future steps to accelerate personalized therapy application

Master protocols, including basket trials, umbrella trials, and (adaptive) platform trials, aim to

further accelerate the application and evaluation of various (repurposed) therapies for

different diseases. These protocols increase efficiency and flexibility by moving away from

the one-disease-one-rug paradigm. Furthermore, many therapies are already being provided

to patients with rare diseases within clinical care settings. It is likely to grow with

advancements such as the Treatabolome (den Hollander et al., 2025) , launched by the

European Joint Programme on Rare Diseases (EJPRD), which gives clinicians a resource to

identify available treatments for rare genetic diseases. However, it is rarely reported whether

a treatment is beneficial to the patient when conducted in care setting.

At the ECPM Therapy Clinic, we systematically evaluate before or without treatment

(serving as natural course data or a baseline) and during treatment for individuals with rare

diseases. These evaluations are consolidated in a database, enabling initial conclusions

about the effectiveness of various therapies for specific rare diseases and across different

conditions.

We are compelled to think and act differently when it comes to rare diseases, from

which we can derive lessons for evidence-based medicine in general. Additionally, specific causes of rare diseases can lead to discoveries about mechanisms that we would not be

able to identify as effectively otherwise. We can accelerate the delivery of treatments to

patients (whether for rare or more common diseases) by applying methodologies arisen in

the field of rare diseases.

References

den Hollander, B., Hoytema van Konijnenburg, E. M., Hewitson, B., van der Meijden, J. C.,

Balfoort, B. M., Winter, B., Müller, A. R., Wasserman, W. W., Ferreira, C. R., & van

Karnebeek, C. D. (2025). The Metabolic Treatabolome and Inborn Errors of Metabolism

Knowledgebase therapy tool: Do not miss the opportunity to treat! Journal of Inherited

Metabolic Disease, 48(1), e12835. https://doi.org/https://doi.org/10.1002/jimd.12835

den Hollander, B., Rothuizen-Lindenschot, M., Geertjens, L., Vaz, F. M., Brands, M. M., Le,

H. L., &..., & Van Karnebeek, C. D. (2023). Effectiveness of L-serine supplementation in

children with a GRIN2B loss-of-function mutation: Rationale and protocol for single patient (n-of-1) multiple cross-over trials. Contemporary Clinical Trials Communications,

36(101233).

Müller, A. R., Den Hollander, B., Van de Ven, P., Roes, K. C. B., Geertjens, L., Bruining, H.,

Van Karnebeek, C. D. M., Jansen, F. E., De Wit, M. C. Y., Ten Hoopen, L. W., Rietman,

A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M. G., & Van Eeghen, A. M.

(2024). Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with

tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome:

protocol for a series of randomized, placebo-controlled N-of-1 trials. BMC Psychiatry,

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Müller, A. R., Zinkstok, J. R., Rommelse, N. N. J., van de Ven, P. M., Roes, K. C. B., Wijburg,

F. A., de Rooij-Askes, E., Linders, C., Boot, E., & van Eeghen, A. M. (2021).

Methylphenidate for attention-deficit/hyperactivity disorder in patients with

Smith–Magenis syndrome: protocol for a series of N-of-1 trials. Orphanet Journal of

Rare Diseases, 16(1). https://doi.org/10.1186/s13023-021-02003-z

Van Eeghen, A. M., Bruining, H., Wolf, N. I., Bergen, A. A., Houtkooper, R. H., Van Haelst, M.

M., & Van Karnebeek, C. D. (2022). Personalized medicine for rare neurogenetic

disorders: can we make it happen? Cold Spring Harb Mol Case Stud, 8(2), a006200.

About the Authors

Dr. Annelieke Müller is assistant professor at the Amsterdam University Medical Center

(UMC) – Emma Center for Personalized Medicine (ECPM).

Her area of expertise is in methodologies to accelerate (targeted) therapy application and evaluation for rare diseases, including (personalized) trial designs and outcome measures.

Dr. Jan Sprengers is child- and adolescent psychiatrist and assistant professor at the ECPM at the Amsterdam UMC. He is committed to developing targeted treatments for children with impaired neurodevelopment.

Dr. Sandra van ‘t Padje is assistant professor and manager at the ECPM at the Amsterdam UMC. She has a background in both scientific research and policy in healthcare development and has a coordinating role in executing strategic policy.

Prof. dr. Hilgo Bruining is child- and adolescent psychiatrist, professor in neurobiological developmental disorders at the Amsterdam UMC and Level, head of the N=You neurodevelopmental precision center, and board member of the ECPM. He focuses on the development and implementation of personalized mechanism-based treatments for

neurodevelopmental disorders.

Prof. dr. Mieke van Haelst is clinical geneticist, Professor & Head of Clinical Genetics, department of human genetics, and co-founder of the ECPM at the Amsterdam UMC. She is highly experienced in pediatric genetics, congenital abnormalities, obesity disorders,

innovative diagnostics, and identification of new genetic causes of rare disorders.

Prof. dr. Clara van Karnebeek is pediatrician metabolic diseases, biochemical geneticist, Professor of Personalized Medicine for genetic metabolic diseases, and co-founder of the ECPM at the Amsterdam UMC. She focuses on early diagnosis, innovative therapies, and

personalized care for rare genetic disorders and inherited metabolic disorders.