Biomarkers and outcome measures in Hurler syndrome (MPS I-H)
Reliable biomarkers and outcome measures underpin both preclinical and clinical investigation in Hurler syndrome, the severe form of MPS I. They provide the critical link between molecular correction, improvement at the organ level, and real-world patient experience, and are central to evaluating HSCT, enzyme replacement, and advanced approaches such as systemic gene therapy.
This page outlines key biochemical, histological, imaging, functional, and clinical outcome domains used in MPS I-H research, with particular emphasis on endpoints commonly applied in preclinical gene therapy studies and their translation into human trials.
linked to outcome data
Why biomarkers and outcomes matter
Although the enzymatic defect in MPS I-H is clearly defined, disease manifestations span multiple organs and involve the central nervous system. No single measurement captures this complexity. Carefully selected biomarkers and outcomes are therefore required to:
- Demonstrate correction of IDUA deficiency and abnormal glycosaminoglycan accumulation.
- Show that molecular and biochemical changes translate into structural and functional benefit.
- Enable meaningful comparison between standard therapies and emerging treatment strategies.
- Support dose selection, trial design, and regulatory evaluation of advanced therapeutic programmes.
Scientific background · Current standard of care · Translational roadmap
Enzyme activity and glycosaminoglycans
IDUA enzyme activity
- Measurement of alpha-L-iduronidase activity in leukocytes or plasma.
- In animal models, assessment across serum and multiple organs including liver, spleen, heart, and brain.
- Used to confirm biological activity and relate enzyme levels to downstream biochemical and clinical effects.
Glycosaminoglycan storage markers
- Total GAG quantification in urine, plasma, or serum.
- Analysis of heparan sulfate and dermatan sulfate species, including disaccharide profiling.
- Tissue GAG measurements in key organs and skeletal compartments in preclinical studies.
Cellular and organ level correction
- Histological assessment of lysosomal storage in liver, spleen, heart, CNS, and other affected tissues.
- Evaluation of cartilage and bone architecture, including growth plates and trabecular structure.
- Central nervous system analyses covering neuronal storage, glial activation, and white matter changes.
- Use of semi-quantitative scoring systems and, where possible, digital image-based quantification.
From enzyme correction to behaviour and survival
- Overall survival and time to humane endpoint.
- Motor and strength testing, including rotarod, grip strength, and gait analysis.
- Activity, coordination, and exploratory behaviour assessments.
- Learning and cognitive tasks where model systems permit.
- Growth patterns and longitudinal body weight tracking.
Translating structural change from models to clinic
Cardiac and respiratory domains
- Echocardiographic assessment of valve disease and ventricular function.
- Advanced imaging such as cardiac MRI in research settings.
- Pulmonary function testing and sleep studies for airway involvement.
CNS and skeletal imaging
- Brain MRI evaluating white matter changes and ventricular size.
- Cervical spine imaging for canal narrowing and cord compression.
- Radiographic scoring of skeletal disease and micro-CT in preclinical work.
Survival, neurocognition and somatic morbidity
Survival and HSCT outcomes
Overall and event-free survival, graft success, chimerism, and need for re-transplantation.
Neurodevelopment and cognition
Developmental assessments in early life and standardised cognitive testing across age groups.
Somatic organ involvement
Cardiac, respiratory, skeletal, visual, and auditory outcomes and associated interventions.
Function and quality of life
Mobility, daily activities, educational participation, and patient- or parent-reported measures.
Bringing multiple measures together
- Use of core outcome sets combining biochemical, survival, cognitive, and organ-specific measures.
- Tiered frameworks distinguishing primary, secondary, and exploratory endpoints.
- Alignment with regulatory expectations and patient priorities.
- Compatibility with registries to enable long-term follow-up.
Biomarkers and outcomes in gene therapy trials
Primary endpoints
Safety, tolerability, enzyme activity, and GAG reduction as pharmacodynamic indicators.
Key secondary endpoints
Organ-specific outcomes and early functional or neurodevelopmental signals.
Long-term follow-up
Durability of benefit, survival, malignancy surveillance, and evolving organ function.
Rationale for gene therapy · Preclinical gene therapy programme · Safety and biodistribution
Making outcomes comparable across studies
- Adoption of standardised definitions and validated tools.
- Alignment between trial endpoints and registry data fields.
- Inclusion of patient- and family-reported outcomes.
- Data sharing to support pooled and meta-analytic approaches.
Biomarkers and outcomes at a glance
- Biochemical markers are essential but must link to tissue and organ outcomes.
- Histology, imaging, and functional measures provide translational evidence.
- Clinical outcomes span survival, cognition, organ morbidity, and quality of life.
- Composite endpoints and registries are critical for long-term comparison of therapies.
Efficacy outcomes
Behavioural, biochemical, and histological endpoints
Safety and biodistribution
Off-target effects and tissue distribution
Scientific background
Pathophysiology and disease mechanisms
Long term outcomes
Survival and organ outcomes after treatment
Follow up and registries
Real-world evidence and data capture
Research priorities
Key open questions across disease domains