Research priorities in Hurler syndrome (MPS I-H)
Hurler syndrome (severe MPS I, MPS I-H) continues to present major unmet clinical challenges despite advances such as haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). This page defines key research priorities across fundamental biology, translational development, clinical outcomes and health services research to support those shaping the next generation of studies.
These priorities can be used to inform grant writing, study design, registry development and strategic planning across academic, clinical and industry settings.
Brain · Bone · Heart · DNA
Why research priorities matter in MPS I-H
MPS I-H is an ultra-rare, multisystem condition that demands significant clinical, research and healthcare resources. Clearly defined priorities help ensure that limited funding, trial capacity and patient participation are directed towards work with the greatest potential impact on survival, function and quality of life.
- Concentrating effort on questions that cannot be addressed through routine care alone.
- Aligning basic, translational and clinical research around shared objectives.
- Supporting funders, regulators and ethics committees in assessing proposals.
- Promoting collaboration rather than duplication across centres and countries.
CNS involvement, neurocognition and brain-targeted therapies
Despite early HSCT, many individuals with MPS I-H experience ongoing neurocognitive impairment and other central nervous system manifestations. Improving understanding and modification of CNS disease remains a central research priority.
- Mechanisms by which IDUA deficiency and GAG accumulation drive neuronal, glial and white-matter pathology.
- Identification of biomarkers and imaging tools that sensitively track CNS disease and treatment response.
- Optimisation of systemic and CNS-directed gene or cell therapies for durable brain correction.
- Evaluation of combined HSCT, ERT and advanced approaches on neurodevelopmental trajectories.
Improving musculoskeletal outcomes
Skeletal disease, chronic pain and mobility limitations are major drivers of long-term disability in MPS I-H and are often only partially corrected by existing therapies.
- Cellular and biomechanical drivers of dysostosis multiplex despite biochemical correction.
- Development of robust measures to capture skeletal progression and treatment response.
- Assessment of surgical strategies and emerging therapies to preserve function and comfort.
- Evaluation of physiotherapy, rehabilitation and assistive technologies as evidence-based interventions.
Reducing cardiopulmonary morbidity and mortality
Cardiac valve disease, cardiomyopathy and respiratory complications remain significant causes of illness and premature death across the lifespan in MPS I-H.
- Comparison of cardiac and respiratory trajectories by treatment strategy, age and genotype.
- Optimisation of surveillance protocols that balance sensitivity with real-world feasibility.
- Use of advanced imaging, biomarkers and functional testing to predict outcomes.
- Strategies to quantify and reduce perioperative and anaesthetic risk.
Refining standard of care as the foundation for innovation
HSCT and ERT remain the backbone of disease-modifying treatment. Continued optimisation is essential even as novel gene and cell therapies advance.
- Long-term comparative outcomes of different HSCT regimens, donor sources and ERT strategies.
- Refinement of timing and sequencing to maximise benefit while minimising risk.
- Identification of biomarkers predicting HSCT benefit and toxicity in borderline cases.
- Integration of HSCT and ERT with emerging therapies in combination or stepwise models.
Translating gene therapy into durable clinical benefit
Systemic gene therapy has the potential to deliver sustained, body-wide IDUA expression following a single or limited intervention.
- Optimisation of vector design, promoters and dosing for efficacy, safety and scalability.
- Selection of preclinical endpoints that best de-risk early human studies.
- Long-term characterisation of biodistribution, immune responses and genomic integration.
- Positioning Hurler syndrome as a model indication for systemic gene delivery platforms.
Capturing long-term impact across the lifespan
High-quality registries and longitudinal cohorts are critical for understanding real-world outcomes, informing clinical practice and evaluating emerging therapies.
- Definition of core outcome sets to ensure consistency and relevance across studies.
- Integration of patient-reported outcomes, cognition and quality-of-life measures.
- Analytic strategies suited to small cohorts, heterogeneity and incomplete data.
- Use of registry data to support health-economic and policy decisions.
Patient-centred and family-centred research
Clinical metrics alone do not capture the full impact of MPS I-H. Research must reflect the lived experience of individuals and families over time.
- Impact on daily life, mental health, education and employment across the lifespan.
- Evaluation of multidisciplinary care, rehabilitation and psychosocial support models.
- Embedding patient and carer perspectives in study design and outcome selection.
- Identifying barriers to accessing care, trials and support across health systems.
Fair access to diagnostics and therapies
As new diagnostics and treatments emerge, equity and global access become increasingly important considerations for the MPS I-H community.
- Expansion of newborn screening and diagnostic pathways in resource-limited regions.
- Frameworks supporting equitable access to HSCT, ERT and gene therapies.
- Ethical approaches to paediatric gene therapy, consent and long-term follow-up.
- International collaboration to reduce fragmentation of evidence and access.
Using these priorities in practice
These priorities are intended as a flexible framework rather than a fixed checklist. Individual projects may span multiple areas simultaneously.
- Use as a reference when developing study concepts or grant applications.
- Position projects within the broader MPS I-H research ecosystem.
- Identify collaborators and complementary expertise.
- Support discussions with patient organisations, funders and regulators.
Key research priorities at a glance
- CNS disease, neurocognition and brain-targeted therapies.
- Skeletal disease, mobility, pain and function.
- Cardiac and respiratory late effects and perioperative risk.
- Optimising HSCT and ERT as the current standard of care.
- Systemic gene therapy and advanced delivery platforms.
- Long-term outcomes, registries and real-world data.
- Lived experience, psychosocial impact and service models.
- Ethics, equity and global access.
For researchers – overview
Audience, themes and core resources.
Research Hub
Scientific background, translational work and roadmap.
Preclinical programme
Models, vector design and outcomes.
Unmet need
Why better therapies remain essential.
Follow-up and registries
Longitudinal data across the lifespan.
Clinical trials & publications
Evidence base and trial context.