Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study

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.