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Convection perfusion of glucocerebrosidase for neuronopathic Gaucher's disease.

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Convection Perfusion of Glucocerebrosidase
for Neuronopathic Gaucher’s Disease
Russell R. Lonser, MD,1 Stuart Walbridge, BS,1 Gary J. Murray, PhD,2 Michele R. Aizenberg, MD,1,3
Alexander O. Vortmeyer, MD,1 Johannes M. F. G. Aerts, PhD,4 Roscoe O. Brady, MD,2
and Edward H. Oldfield, MD1
Systemic enzyme replacement for Gaucher’s disease has not prevented premature death or severe morbidity in patients
with a neuronopathic phenotype, because the enzyme does not cross the blood–brain barrier. We used convectionenhanced delivery for regional distribution of glucocerebrosidase in rat and primate brains and examined its safety and
feasibility for neuronopathic Gaucher’s disease. Rats underwent intrastriatal infusion and were observed and then sacrificed at 14 hours, 4 days, or 6 weeks. Primates underwent serial magnetic resonance imaging during enzyme perfusion
of the right frontal lobe or brainstem, were observed and then sacrificed after infusion completion. Animals underwent
histologic and enzymatic tissue analyses. Magnetic resonance imaging revealed perfusion of the primate right frontal lobe
or pons with infusate. Enzyme activity was substantially and significantly (p < 0.05) increased in cortex and white matter
of the infused frontal lobe and pons compared to control. Immunohistochemistry demonstrated intraneuronal glucocerebrosidase. There was no toxicity. Convection-enhanced delivery can be used to safely perfuse large regions of the brain
and brainstem with therapeutic levels of glucocerebrosidase. Patients with neuronopathic Gaucher’s disease and similar
central nervous system disorders may benefit from this treatment.
Ann Neurol 2005;57:542–548
Gaucher’s disease is the most prevalent hereditary
metabolic storage disorder. It is caused by insufficiency of glucocerebrosidase, the gene for which is located on the long arm of chromosome 1. Glucocerebrosidase is located in lysosomes where it catabolizes
the glycolipid glucocerebroside,1 which is produced
from phagocytosed cell membranes. Deficiency of
glucocerebrosidase results in the pathological accumulation of glucocerebroside in the lysosomes of Gaucher’s cells (monocyte-derived macrophages) and in
neurons in the central nervous system (CNS).2 Abnormal accumulation of Gaucher’s cells and glucocerebroside results in anemia and thrombocytopenia,
hepatosplenomegaly, skeletal abnormalities, and, in
some patients, neuronal damage.
Gaucher’s disease is categorized into three clinical
types (types 1, 2, and 3) based on the pace of progression and presence of neuronal involvement. In
type 1 (nonneuronopathic variant), the CNS is not
involved. Type 2 (acute neuronopathic variant) is
universally progressive and rapidly fatal because of
rapid neurological deterioration (cranial nerve and extrapyramidal dysfunction). Type 3 (subacute or
chronic neuronopathic variant) has variable degrees of
systemic and neurological involvement, and its progression is more insidious. Although intravenous glucocerebrosidase replacement therapy is now used to
reverse and halt the progression of Gaucher’s disease
outside the CNS,3–7 it has not slowed the progression
or severity of neurological deterioration in patients
with type 2 or 3 Gaucher’s disease.
The lack of effectiveness using systemic enzyme replacement therapy to treat neurological deterioration in
Gaucher’s disease results from the inability of intravenously administered glucocerebrosidase to cross the
blood–brain barrier (BBB) in therapeutic amounts.5,6,8,9
To overcome this limitation, we investigated the potential of convection-enhanced delivery (CED)10 to perfuse
the brain and brainstem with therapeutic levels of glucocerebrosidase.
From the 1Surgical Neurology Branch and 2Developmental and
Metabolic Neurology Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD;
3
Department of Neurosurgery, George Washington University
Medical Center, Washington, DC; and 4Department of Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Published online Mar 28, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20444
Address correspondence to Dr Lonser, Surgical Neurology Branch,
National Institute of Neurological Disorders and Stroke, National
Institutes of Health, Building 10, Room 5D37, Bethesda, MD
20892-1414. E-mail: lonserr@ninds.nih.gov
Received Dec 17, 2004, and in revised form Feb 8, 2005. Accepted
for publication Feb 9, 2005.
542
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Materials and Methods
Animal procedures were performed in accordance with the
regulations of the Animal Care and Use Committee of the
National Institute of Neurological Disorders and Stroke.
Enzyme Infusate
Recombinant mannose-terminal glucocerebrosidase (molecular weight, 60kDa; Cerezyme; Genzyme Corporation, Framingham, MA) was dissolved in 10mM sodium phosphate,
135mM sodium chloride, and 5mg/ml human serum albumin to a concentration of 2mg/ml at pH 7.0 (enzyme activity, 79U/ml).
Rat Toxicity Studies
Glucocerebrosidase was infused using CED into the right
striatum of 12 male Sprague–Dawley rats.11 Animals were
killed at 14 hours (n ⫽ 4), 4 days (n ⫽ 4), or 6 weeks (n ⫽
4). The brains were frozen (⫺80°C), cut into 20-␮m-thick
sections, and stained with hematoxylin and eosin (all survival
groups) or used for immunohistochemical analysis (14-hour
survival group) with a monoclonal antibody for the recombinant form of glucocerebrosidase.
the infusion cannula was placed stereotactically in the midpons.
NEUROLOGICAL OBSERVATION. Animals undergoing
chronic infusion (those undergoing perfusion of the right
frontal lobe; n ⫽ 3) were evaluated twice daily during infusion and were killed 48 hours after infusion initiation.
The animal that underwent brainstem infusion was awakened from general anesthesia after completion of the 3-hour
infusion, and then was observed for 30 minutes for neurological deficits before being killed.
HISTOLOGICAL AND IMMUNOHISTOLOGICAL ANALYSIS.
Primates were killed by intravenous pentobarbital (90mg/kg)
and perfused with chilled (4°C) saline. Brains were cut into
coronal blocks (5–10mm in thickness). Sections from these
blocks were cut (10␮m in thickness) and stained with hematoxylin and eosin, or used for recombinant glucocerebrosidase immunohistochemistry. A neuropathologist (A.O.V.)
determined identification of cortical neurons by typical morphological criteria (ie, overall size, the presence of a large
nucleus, prominent nucleoli, and abundant cytoplasm).
Primates
IMAGING. Stereotactic coordinates for
placement of the infusion cannula in the center of the right
frontal white matter (n ⫽ 3) or pons (n ⫽ 1) in primates
(Macaca mulatta) were obtained from preoperative magnetic
resonance imaging (MRI).
PREOPERATIVE
CONVECTION-ENHANCED DELIVERY OF ENZYME TO THE
RIGHT FRONTAL LOBE. Animals were sedated, intubated,
and placed under general anesthesia. After placement in the
stereotactic head frame, an anterior–posterior midline incision was made over the vertex, and a burr hole was placed
over the right frontal region. A cannula was inserted stereotactically (28-gauge fused silica; inner diameter,
0.152mm; outer diameter, 0.360mm; Plastics One,
Roanoke, VA) into the right frontal white matter, connected to thin-walled polyvinyl 60 tubing (inner diameter,
0.72mm; outer diameter, 1.22mm; Plastics One), and secured to the skull using methylmethacrylate. The polyethylene tubing attached to the cannula was tunneled under
the scalp posteriorly and exited out the skin near midline at
the midscapular level. The tubing was attached to a programmable microinfusion pump (Model 404-SP; MiniMed
Technologies, Sylmar, CA) for continuous convective infusion of enzyme over 48 hours. The animals were placed
into a custom-made vest (Lomir Biomedical, Quebec, Canada) that housed the infusion pump. The infusate syringe
was replaced every 8 to 12 hours. The rate of infusion varied
from 1 to 2␮l/min based on the distribution of infusate seen
on serial MRI (T1- and T2-weighted and fluid-attenuated inversion recovery images in the axial and coronal planes; 3mm
in thickness without spacing).
CONVECTION-ENHANCED DELIVERY OF ENZYME TO THE
BRAINSTEM (PONS). The procedures and MRI for this an-
imal were identical to the description above, except the tip of
ASSAY OF GLUCOCEREBROSIDASE ACTIVITY. Samples (approximately 3mm cubes) from both cortices, white matter,
or both were cut from the tissue blocks of harvested primate
brains, brainstem, or both. Samples were weighed and extracted by sonication (10 seconds) in a buffer of 6.1mM citric acid and 21mM disodium phosphate, pH 6.0 containing
2% Triton X-100 (Sigma; St. Louis, MO) and 1% sodium
taurocholate. After centrifugation at 21,000g for 30 minutes,
the supernatant was assayed for glucocerebrosidase activity
fluorometrically. Samples (10␮l each) were incubated for
10 minutes at 37°C in a final volume of 200␮l of 15mM
4-methylumbelliferylglucopyranoside (Sigma) in pH 5.9
buffer containing 0.1M potassium phosphate, 0.15% Triton
X-100, 0.125% sodium taurocholate, and 0.1% bovine serum albumin and were stopped by the addition of 800␮l of
0.1N sodium hydroxide and 0.1N glycine.
Statistical analysis was performed
on Microsoft Excel X (Microsoft, Redmond, WA) software
text.
STATISTICAL ANALYSIS.
Results
Rodent Studies
All rats tolerated the infusion without clinical evidence
of toxicity over the observation period. Histological
analysis demonstrated normal tissue architecture with
mild focal inflammation confined to the region immediately adjacent (maximum radius, 50␮m) to the cannula tract. Immunohistochemical staining for glucocerebrosidase (14-hour survival group) demonstrated a
substantial increase in intraneuronal enzyme staining in
the striatum and cortex on the infused side compared
with the uninfused side.
Lonser et al: Convection of Glucocerebrosidase
543
Primate Studies
REAL-TIME MAGNETIC RESONANCE IMAGING DURING INFUSION. Real-time, T2-weighted, and fluid-attenuated
inversion recovery MRI performed during infusion indicated progressive and complete filling of the right
frontal lobe (anterior 2cm of the right cerebral hemisphere; n ⫽ 3; Fig 1) or pons (n ⫽ 1). In the animals
that underwent right frontal lobe perfusion, infusate
was distributed in the frontal white matter surrounding
the cannula tip by infusion day 1 (see Fig 1). By infusion day 2, the region of infusion was seen extending
to and through the overlying associated cortex (see Fig
1). Because of its smaller volume, complete perfusion
of the pons was accomplished in 3 hours, as demonstrated on MRI.
CLINICAL EFFECTS OF INFUSION. None of the primates
demonstrated neurological deficits or adverse clinical
symptoms during or after the infusions.
GROSS AND HISTOLOGICAL ANALYSIS. Gross examination of the animal brains showed normal weight and
architecture. Brain and brainstem sections prepared
with hematoxylin and eosin demonstrated normal tissue structure and mild focal inflammation limited to a
radius of 50 to 100␮m around the infusion cannula
tract.
GLUCOCEREBROSIDASE ACTIVITY. Glucocerebrosidase
activity assays from the cortex and white matter of
the perfused right frontal lobes (n ⫽ 3) showed substantially increased activity compared with the uninfused left frontal lobes (n ⫽ 3) (Fig 2). A significant
(Wilcoxon paired test, p ⬍ 0.05) increase in activity
(both in gray and white matter) was distributed
throughout the infused lobe compared with the corresponding regions of the uninfused lobe (see Fig 2).
Posterior to the perfused frontal lobe, there was no
significant difference between sides in gray or white
matter enzyme activity. Activity assays throughout the
perfused pons showed significantly (Wilcoxon paired
test, p ⬍ 0.05) increased glucocerebrosidase activity
compared with pontine tissue from an uninfused animal (Fig 3).
Immunohistochemical staining for glucocerebrosidase in the perfused
cortical regions (right frontal lobe infusions) demonstrated a substantial increase in intracytoplasmic neuronal staining for glucocerebrosidase compared with the
uninfused left frontal lobe (Fig 4).
GLUCOCEREBROSIDASE LOCALIZATION.
Discussion
Intracerebral Delivery of Glucocerebrosidase
Despite the successful treatment of the systemic manifestations of Gaucher’s disease by intermittent intrave-
Fig 1. T2-weighted, axial, magnetic resonance imaging of a nonhuman primate brain performed on infusion days 1 and 2. (Left)
Imaging on infusion day 1 shows perfusion of the right frontal white matter with infusate (white hyperintensity). (Right) Imaging
on infusion day 2 shows progressive filling of the white matter tracts with infusate (white hyperintensity), which now extends into
the overlying frontal cortex.
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Fig 2. (A) Bar graphs representing glucocerebrosidase activity in
the cortex (gray matter) of the infused (right cerebral hemisphere;
black bars) and uninfused (left cerebral hemisphere; gray bars)
primate brain after 48 hours of convection-enhanced delivery of
glucocerebrosidase. Enzyme activity for both the experimental (infused) and control (uninfused) sides were measured in nanomoles
of substrate converted per hour per microliter tissue. Glucocerebrosidase activity in the right frontal lobe (anterior 2cm of the cerebral hemisphere) cortex of the experimental side (infused) was
significantly higher than the control side (uninfused) (Wilcoxon
paired test, p ⬍ 0.05). Posterior to the perfused frontal lobe
(⬎2cm from the tip of the cerebral hemisphere), there was no
significant difference in gray or white matter enzyme activity compared with the corresponding region of the uninfused side (Wilcoxon paired test, p ⬎ 0.05). (B) Bar graphs representing glucocerebrosidase activity in the white matter of the infused (right
cerebral hemisphere; black bars) and uninfused (left cerebral
hemisphere; gray bars) primate brain after 48 hours of
convection-enhanced delivery of glucocerebrosidase. Glucocerebrosidase activity in the right frontal lobe (anterior 2cm of the cerebral
hemisphere) white matter of the experimental side (infused) was
significantly higher than the control side (uninfused) (Wilcoxon
paired test, p ⬍ 0.05). Posterior to the perfused frontal lobe
(⬎2cm from the tip of the cerebral hemisphere), there was no
significant difference in gray or white matter enzyme activity compared with the corresponding region of the uninfused side (Wilcoxon paired test, p ⬎ 0.05).
nous glucocerebrosidase administration, the progression
or severity of neurological symptoms in neuronopathic
patients has not been slowed because of the inability of
intravenously delivered glucocerebrosidase to cross the
BBB. Previous attempts to distribute glucocerebrosidase
into the brain through intraventricular delivery12 or
BBB disruption13 with intravascular coinjection of enzyme resulted in delivery of therapeutically inadequate
amounts of enzyme and were subsequently abandoned.
To overcome these limitations, we investigated the
use of CED to perfuse the primate brain with glucocerebrosidase. CED relies on bulk flow driven by a
small continuous pressure source to distribute molecules within the interstitial space of tissue. Unlike intraventricular delivery and other delivery approaches
that rely on diffusion for distribution, CED is not limited by the molecular weight, concentration, or diffusive properties of the infusate.10,14 –16 CED permits
distribution of molecules directly within brain parenchyma through a cannula and can be used to target
selected regions of the CNS in a manner that bypasses
the BBB.10,14,15,17 Because CED preferentially distributes infusate along white matter tracts,14,15 it can be
used to take advantage of these low-resistance pathways
to perfuse large regions of cerebral cortex from a point
source. Previous studies have shown that CED can be
used to distribute small and large molecules throughout the CNS safely and homogeneously over a wide
range of tissue volumes that are related to the extracellular fluid fraction in the infused region.10,18,19
The optimal delivery method for distribution of glucocerebrosidase to the CNS for the treatment of neuronopathic Gaucher’s disease must have several features. Delivered enzyme activity must be provided
Fig 3. Bar graph representing glucocerebrosidase activity in the
pons of an infused primate versus the pons of an uninfused
primate after 3 hours of convection-enhanced delivery of glucocerebrosidase. Enzyme activity for the experimental (infused)
and control (uninfused) animals were measured in nanomoles
of substrate converted per hour per microliter tissue. Glucocerebrosidase activity in the infused pons was significantly higher
than the control pons (uninfused) (Wilcoxon paired test, p ⬍
0.05).
Lonser et al: Convection of Glucocerebrosidase
545
Fig 4. Immunohistochemistry for glucocerebrosidase performed on coronal sections from the infused and uninfused primate frontal
lobe after a 48-hour right frontal lobe infusion. (Left) The control (uninfused; left frontal lobe) side demonstrates cortical neurons
with absent or faint intracytoplasmic staining. (Right) The infused (right frontal lobe) side demonstrates dark (brown) intracytoplasmic cortical neuron staining.
safely at effective levels. Active enzymes must be delivered to the affected areas, including deep brain nuclei,
the brainstem, or large regions of cortical neurons. The
interstitial enzyme must be internalized into neurons
for effective elimination of the pathological metabolites. Noninvasive imaging techniques will be critical to
ascertain adequate delivery and to determine the effectiveness of therapy.
Although an animal model of Gaucher’s disease
could be instructive in developing a CED-based therapeutic paradigm, no neuronopathic animal model has
been described that survives beyond the immediate
neonatal period.20 Based on preliminary work in rodents,16 which showed that acute convective infusion
of placental glucocerebrosidase could be used to perfuse
neurons, we examined the use of CED for distribution
of recombinant glucocerebrosidase in the brain of rats
and primates.
Current Study
REAL-TIME IMAGING. MRI indicated progressive and
complete filling of the right frontal lobe (see Fig 1) or
the pons with infusate in primates. The distribution of
the glucocerebrosidase infusate, as shown on MRI, was
confirmed by immunohistochemical and enzymatic assays. The ability to track infusate distribution during
drug delivery will be important for ensuring effective
distribution, and it should facilitate establishment of
the optimal delivery rate and cannula placement in
clinical studies.
The perfused region
of the primate brain and brainstem demonstrated significant increases in glucocerebrosidase activity compared with control tissues. This was the case for the
perfused white matter and the cortex (gray matter; see
GLUCOCEREBROSIDASE ACTIVITY.
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Fig 2) and pons (see Fig 3) compared with the uninfused tissues. The increased glucocerebrosidase activity
assayed in these animals represents enzymatic activity
in perfused interstitial spaces and intracellular enzyme
activity, as demonstrated in the cortical neurons (see
Fig 4).
Previous studies have examined native glucocerebrosidase activity in healthy human brains and the brains
of patients with Gaucher’s disease (types 1, 2, and 3).
Whole-brain homogenates (unlike the primate assays in
this study, where white matter and cortex were separated) showed that glucocerebrosidase activity ranges
from 3 to 4nmol/hr/␮l tissue in the healthy brain,
whereas the enzyme activity is in the range of 0.1 to
0.6nmol/hr/␮l tissue in Gaucher’s disease brains.21,22
The supraphysiological levels of active enzyme achieved
in the primate brains in this study suggest that, using a
similar approach, clinically effective levels of glucocerebrosidase activity could be provided to neuronopathic
Gaucher’s disease patients.
Immunohistochemical staining for glucocerebrosidase demonstrated
increases in cytoplasmic staining for the enzyme in the
neurons of the cortex on the infused side. This increased staining confirms that the infused glucocerebrosidase reached the cerebral cortex and was taken up
by cortical neurons (see Fig 4). The mechanism of cellular uptake of glucocerebrosidase is through highly efficient mannose receptor–mediated endocytosis.23
Mannose receptors are found on neurons, astrocytes,
and microglia,16,23,24 and they should allow effective
uptake of convectively distributed glucocerebrosidase in
all of these CNS cell types.
GLUCOCEREBROSIDASE LOCALIZATION.
Short-term and prolonged convective delivery
of glucocerebrosidase was safe. None of the animals
displayed neurological signs or behavioral changes over
the course of the study. Corroborating these clinical
findings, histological analysis of infused tissue sections
demonstrated normal tissue architecture with minimal
inflammation in the area immediately adjacent (maximum radius, 100␮m) to the infusion cannula.
SAFETY.
FUTURE APPLICATIONS. Intracerebral CED of glucocerebrosidase may be a treatment option for neuronopathic Gaucher’s disease patients used in conjunction
with intravenous therapy for treatment of the systemic disease processes. Because glucocerebroside production and buildup in the brain is maximal in the
neonatal period in neuronopathic Gaucher’s disease,
after a reduction of enzyme accumulation by direct
convective perfusion of glucocerebrosidase, subsequent treatments may be required only intermittently
every several years. A potential concern related to this
intermittent infusion paradigm is the possible accumulation of intracellular ceramide, which is a proapoptotic metabolic byproduct of the break down of
glucocerebroside. However, buildup of ceramide is
unlikely to occur because naturally occurring intracellular ceramidase should convert the majority of this
toxic metabolite into sphingosine and fatty acid.
Moreover, any remaining ceramide likely will be converted to sphingomyelin by ceramide cholinephosphotransferase.
Conclusions
This study shows that CED can be used to distribute
glucocerebrosidase to the brain, overcoming the previous limitations of other delivery methods. These findings suggest that intracerebral CED of glucocerebrosidase may be a treatment option for neuronopathic
Gaucher’s disease patients when used in conjunction
with intravenous therapy for treatment of the systemic
disease processes. A similar treatment approach in
which the white matter tracts are used to provide rapid
and widespread drug distribution to brainstem and cerebral white matter and cortex may be useful for other
disorders affecting large regions of the CNS, including
other metabolic storage diseases and degenerative diseases.
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