Objective: To evaluate the effects of intravenous enzyme
replacement with rhASA in children with late infantile MLD.
Background: Several lysosomal storage diseases are successfully
treated with intravenous enzyme replacement therapy.
Design: Thirteen children (5M/8F; median age 34 months)
were enrolled in a Phase I/II dose-escalation enzyme replacement
trial; enzyme was administered intravenously biweekly
in three dose cohorts. Endpoints included assessments of
motor and cognitive function, MRI score, demyelinated white
matter volume, brain metabolites by MR spectroscopy, CSF
sulfatide levels, neurophysiological tests, and sural nerve
morphology and (lyso)sulfatide levels. Evaluations occurred
at baseline, 26 and 52 weeks.
Results: Eleven children completed the trial; 2 withdrew due
to disease progression at Weeks 18 and 30, respectively.
Enzyme infusions were well tolerated in general. Motor
and cognitive function progressively deteriorated in all
children during the trial without any apparent enzyme
dose effects. Likewise, no dose dependent responses were
observed for sural nerve morphology, neuroradiological
and neurophysiological assessments. Although a durable
reduction in CSF sulfatide levels was observed at Weeks 26
and 52 in the high dose cohort, this effect was associated
with substantial blood brain barrier leak in 3 patients with
advanced disease. Sural nerve sulfatide and lysosulfatide
levels remained unchanged at Week 26 in all dose groups;
these latter data document absence of clearance of storage
material from a relevant target tissue.
Conclusion: Intravenous delivery of rhASA to nervous system
was insufficient to clear stored sulfatide, prevent further
demyelination and stabilize motor function. Direct delivery
of enzyme to CNS may be beneficial.
|Conference||9th European Paediatric Neurology Society Congress : European Paediatric Neurology Society Congress|
|Period||01/01/2009 → …|