Related Experiment Video
Updated: Nov 25, 2025
An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study
Christine Í Dali1, Samuel Groeschel2, Mihai Moldovan3,4
1Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
Objective:
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA), resulting in severe motor and cognitive dysfunction. This phase 1/2 study evaluated the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA; HGT-1111, previously known as Metazym) in children with MLD.
Methods:
Thirteen children with MLD (symptom onset < 4 years of age) were enrolled in an open-label, nonrandomized, dose-escalation trial and received IV rhASA at 50, 100, or 200 U/kg body weight every 14 (± 4) days for 52 weeks (NCT00418561; NCT00633139). Eleven children continued to receive rhASA at 100 or 200 U/kg during a 24-month extension period (NCT00681811). Outcome measures included safety observations, changes in motor and cognitive function, and changes in nerve conduction and morphometry.
Results:
There were no serious adverse events considered related to IV rhASA. Motor function and developmental testing scores declined during the study in all dose groups; no significant differences were observed between groups. Nerve conduction studies and morphometric analysis indicated that peripheral nerve pathology did not worsen during the study in any dose group.
Interpretation:
IV rhASA was generally well tolerated. There was no evidence of efficacy in preventing motor and cognitive deterioration, suggesting that IV rhASA may not cross the blood-brain barrier in therapeutic quantities. The relative stability of peripheral nerve function during the study indicates that rhASA may be beneficial if delivered to the appropriate target site and supports the development of rhASA for intrathecal administration in MLD.
Insights
Intravenous recombinant human arylsulfatase A (rhASA) was safe for children with metachromatic leukodystrophy (MLD). However, IV rhASA did not prevent motor or cognitive decline, suggesting it does not effectively cross the blood-brain barrier for MLD treatment.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Metachromatic leukodystrophy (MLD) is a severe genetic disorder affecting motor and cognitive functions due to arylsulfatase A (ASA) deficiency.
- Lysosomal storage diseases like MLD require effective therapeutic interventions to manage debilitating symptoms.
Purpose of the Study:
- To assess the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA) in pediatric patients with MLD.
- To evaluate the impact of IV rhASA on motor function, cognitive development, and peripheral nerve health.
Main Methods:
- A phase 1/2, open-label, dose-escalation study involving 13 children with MLD.
- Administration of IV rhASA at escalating doses (50, 100, 200 U/kg) every 14 days for 52 weeks, followed by an extension period.
Main Results:
- IV rhASA was generally well-tolerated with no serious adverse events related to treatment.
- All participants showed continued decline in motor and cognitive function, with no significant differences between dose groups.
- Peripheral nerve pathology did not worsen, indicating potential benefit if delivered to the target site.
Conclusions:
- While IV rhASA is safe, it demonstrated no efficacy in preventing MLD progression, likely due to insufficient blood-brain barrier penetration.
- Findings support further investigation of rhASA for intrathecal administration to target the central nervous system effectively in MLD.
Related Concept Videos
01:24Phase II Reactions: Glucuronidation
01:19Phase II Reactions: Sulfation and Conjugation with α-Amino Acids