TY - JOUR
T1 - Penetration, diffusion, and uptake of recombinant human α-L-iduronidase after intraventricular injection into the rat brain
AU - Belichenko, P. V.
AU - Dickson, P. I.
AU - Passage, M.
AU - Jungles, S.
AU - Mobley, W. C.
AU - Kakkis, E. D.
PY - 2005/9/1
Y1 - 2005/9/1
N2 - Central nervous system disease can have devastating consequences in the severe or Hurler form of mucopolysaccharisosis I (MPS I). Intravenously administered recombinant human α-L-iduronidase (rhIDU) is not expected to reach and treat the brain disease due to the blood-brain barrier. To determine whether administration of rhIDU into the cerebrospinal fluid could successfully treat the brain, we studied intraventricular administration of rhIDU in rats. RhIDU was stereotactically administered directly to the lateral ventricle of the intact rat brain and the brain tissues assessed by enzyme assays, immunofluorescence and confocal microscopy 30 min, 24 h, or 7 days later. Quantitation of activity revealed that rhIDU was widely distributed throughout the brain following injection into the lateral ventricle, with activities increased by a factor of 3.3 higher than control in most samples 30 min-24 h after injection and highest levels on the side of injection. The enzyme crossed the ependymal lining of the ventricle and entered neurons into lysosomal-like vesicles. The enzyme was able to diffuse through brain tissue as demonstrated by a decreasing signal gradient from 0.2 to 4.8 mm from the ventricle surface. The largest amount of rhIDU, as detected by immunostaining, was observed 24 h after injection and decreased approximately 50% during the first 7 days. Although the immunostaining decreased with time, specific vesicular staining was still detectable 28 days after injection. The data suggest that rhIDU given into the ventricle can diffuse, penetrate at least several millimeters of brain tissue and be taken up into neurons and glial cells.
AB - Central nervous system disease can have devastating consequences in the severe or Hurler form of mucopolysaccharisosis I (MPS I). Intravenously administered recombinant human α-L-iduronidase (rhIDU) is not expected to reach and treat the brain disease due to the blood-brain barrier. To determine whether administration of rhIDU into the cerebrospinal fluid could successfully treat the brain, we studied intraventricular administration of rhIDU in rats. RhIDU was stereotactically administered directly to the lateral ventricle of the intact rat brain and the brain tissues assessed by enzyme assays, immunofluorescence and confocal microscopy 30 min, 24 h, or 7 days later. Quantitation of activity revealed that rhIDU was widely distributed throughout the brain following injection into the lateral ventricle, with activities increased by a factor of 3.3 higher than control in most samples 30 min-24 h after injection and highest levels on the side of injection. The enzyme crossed the ependymal lining of the ventricle and entered neurons into lysosomal-like vesicles. The enzyme was able to diffuse through brain tissue as demonstrated by a decreasing signal gradient from 0.2 to 4.8 mm from the ventricle surface. The largest amount of rhIDU, as detected by immunostaining, was observed 24 h after injection and decreased approximately 50% during the first 7 days. Although the immunostaining decreased with time, specific vesicular staining was still detectable 28 days after injection. The data suggest that rhIDU given into the ventricle can diffuse, penetrate at least several millimeters of brain tissue and be taken up into neurons and glial cells.
KW - Brain
KW - Hurler
KW - Lysosomal storage disease
KW - Mucopolysaccharidosis
KW - Rat
KW - Scheie
KW - α-L-Iduronidase
UR - http://www.scopus.com/inward/record.url?scp=26244447178&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2005.04.013
DO - 10.1016/j.ymgme.2005.04.013
M3 - Article
C2 - 16006167
AN - SCOPUS:26244447178
VL - 86
SP - 141
EP - 149
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 1-2
ER -