From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Enzyme Replacement Therapy for Gaucher Disease
By E. Beutler, A. Kay, A. Saven, P. Gamer, D. Thurston, A. Dawson, and B. Rosenbloom
Four patients with moderately severe type I Gaucher disease
were treated with commercially available mannose terminated glucocerebrosidase (Ceredase; Genzyme, Boston, MA)
for up to 13 months. The enzyme was administered at the
rate of three to four times weekly at one fourth the total
recommended dosage, greatly decreasing the cost. Marked
regression of hepatomegaly and improvement in liver func-
tion tests, peripheral blood counts, and serum angiotensinconverting enzyme levels were documented. The two patients with pulmonary involvement manifested improvement
in pulmonary function tests. Skeletal disease remained unchanged.
8 1991 by The American Society of Hematology.
L
Clinical histories. S.W. is a 30-year-old woman of Ashkenazi
Jewish ancestry. The diagnosis of Gaucher disease was made in
1965 at age 5 as a result of evaluation of a bleeding tendency and
splenomegaly. Splenectomy was performed at age 7, and pains in
the hips and knees began at age 8. In succeeding years, she suffered
a fracture of the right hip and compression fracture of the 10th
thoracic vertebra. At age 20, the patient developed progressive
shortness of breath. At age 25, the dyspnea had become so severe
as to limit performance of simple daily activities. Pulmonary
function tests at that time showed decreased steady-state diffusion
capacity of her lungs and a low ventilationlperfusion ratio that was
believed to be due to right-to-left shunting. At bronchoscopy
possible Gaucher-like cells were identified in bronchial washings,
but transbronchial lung biopsy was normal. Since 1988, the patient
had been on continuous nasal oxygen because of severe dyspnea,
limiting even eating and speaking.
On starting enzyme therapy in February 1990 the patient had
massive hepatomegaly, markedly abnormal liver function studies,
and severe dyspnea, even at rest. There was mild reduction in the
static lung volumes that was probably explained by her small chest
size relative to her height because her lung elastic recoil pressure
and status lung compliance were normal. She had very severe
hypoxemia that may have been largely due to right-to-left shunting,
although a reduced pulmonary capillary volume was indicated by a
severe and proportional reduction of both the single breath and the
steady-state diffusing capacity. Pertinent findings and clinical
laboratory findings at the beginning of therapy are summarized in
Tables 1and 2.
G.S. is a 45-year-old woman of Ashkenazi Jewish ancestry. She
was first noted to have splenomegaly and easy bruising at age 4.
During childhood she had multiple episodes of bone pain and
difficulty in walking. At age 25, the patient was splenectomized
because of massive enlargement of the spleen. At the beginning of
1990, the patient began noticing shortness of breath. Her resting
oxygen saturation was found to be 90%. Transbronchial biopsy
showed pulmonary involvementwith Gaucher disease. At the start
of enzyme therapy in August 1990 the patient had massive
YSOSOMAL, STORAGE diseases are the result of
deficiencies of enzymes required to degrade complex
molecules in cells. The most common of these disorders is
Gaucher disease, in which glucocerebroside accumulates in
macrophages because of a deficiency of the lysosomal
p-glucosidase (glucocerebrosidase). Until recently, treatment of Gaucher disease has been almost entirely symptomatic. An exception is the use of allogeneic bone marrow
transplantation, which cures the reticulo-endothelial manifestations of the disease,'-3but at a high risk, which makes it
an unsuitable modality in most cases, even when a matching
donor is available.
In 1964 De Duve4suggested that the lysosomal disorders
might yield to enzyme replacement. Among the lysosomal
storage diseases, Gaucher disease has been considered a
prime candidate for such therapeutic intervention because
the nervous system is usually spared and because cells of
the macrophage system seem ideally suited to take up
exogenously administered substances. Although a number
of attempts to treat Gaucher disease by enzyme replacement were made in the 1970s, these were unsuccessful.
They were probably doomed to failure partly because of an
inadequate supply of
The enzyme supply problem has been overcome by production of glucocerebrosidase on a commercial scale. Moreover, modification of the
native enzyme to expose mannose residues presumably
improves its targeting to tissue macrophages.","
Although only scant clinical data have previously been
the dose of mannose terminated glucocerebrosidase (Ceredase; Genzyme, Boston, MA) recommended by the manufacturer and most commonly used is 60
U/kg/2 weeks or approximately 1,560 Ukg body weight
annually. This amount of enzyme administered to a 70-kg
patient costs $382,000. Because it seems likely that a
greater amount of enzyme will be delivered to the monocytemacrophage system if it is administered more frequently,
we have treated four patients with less than one fourth of
this dose. Two units per kilogram was administered on
alternate days or 2.3 U k g was given three times weekly. In
this communication we report a very satisfactory response
to enzyme replacement therapy in all patients.
PATIENTS
All patients treated had moderately severe or severe type I
Gaucher disease, confirmed by leukocyte P-glucosidase estimati~n.'~.''All manifested the 1,226/? genotype as described previo ~ s l y .The
' ~ treatment protocol was approved by the Institutional
Review Board of the Scripps Clinic and Research Foundation, and
all patients gave informed consent for enzyme administration and
for the follow-up studies.
Blood, Vol78, No 5 (September 1). 1991: pp 1183-1189
From the Department of Molecular and Eqerimental Medicine,
Research Institute of Scripps Clinic, La Jolla, CA.
Submitted February 13,1991; accepted April 25,1991.
Supported by National Institutes of Health grant Nos. DK36639,
RR00833, and the Sam Stein and Rose Stein Charitable Trust Fund.
This is publication no. 6662-MEM from the Research Institute of
Scripps Clinic.
Address reprint requests to E. Beutler, MD, Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic,
10666 N Torrey Pines Rd, La Jolla, CA 92037.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
8 1991 by TheAmerican Society of Hematology.
0006-4971191/7805-0007$3.0010
1183
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
BEUTLER ET AL
1184
Table 1. Hematologic, Liver Function, and Bone Findings in Four Patients With Gaucher Disease Before and After Treatment With Ceredase
Months of
Treatment
Hemoglobin (g/dL)
Male
Female
Hematocrit (%)
Male
Female
Platelets ( x 1OYfiL)
PT (SI
0
14-18
12-16
P'TT (SI
SGOT U/L
SGPT U/L
GGT U/L
Alkaline phosphatase (U/L)
Total bilirubin (mg/dL)
Direct bilirubin (mg/dL)
ACE (mU/mLserum)
Bone lesions
G.S.
S.W.
Normal
Range
39-55
36-48
130-400
10.4-13.2
22-36
2-40
2-40
4-51
30-120
0.0-1.5
0.0-0.4
16.4-52.4
13
0
A.M.
6
10.3
14.0
14.7
14.8
31
164
14.7
40.3
141
78
148
194
1.2
0.5
324
UHS)
40
246
13.8
40.8
71
67
105
44
112
14.2
38.8
41
22
157
106
0.7
0.4
247
I(F)
44
201
13.5
40.4
56
41
201
117
1.1
0.5
212t
84
1.1
0.3
220'
Stable
Stable
B.F.
6
0
10.3
11.2
29
32
286
14.5
37.5
58
32
50
145
0.5
313
14.5
41.2
31
9
36
137
0.4
0.1
173
0.4
227
I(F)
NR
CompFxl
0
4
5.5
7.9
16.5
50
14.6
59.7
54
17
81
276
0.6
0.3
262
I(H,F)
25
55
14.3
44.0
42
17
42
217
1.2
0.3$
280*
NR
CompFxll
Abbreviations: NR, not repeated; I, infactions;H. humeri; F, femurs; CompFx, compression fractures.
'10 months.
t 4 months.
$1 month.
§Extensiveinvolving thoracic and lumbar spine.
I/lnvolvingthoracic spine only.
hepatomegaly. She had normal static lung volumes and mild airway
obstruction possibly due to mild asthmatic bronchitis. Her steadystate diffusing capacity and her resting arterial oxygen tension were
moderately reduced and she showed mild arterial desaturation to
90% by ear oximetry during exercise. Pertinent clinical and
laboratory findings at the time therapy was started are summarized
in Tables 1and 2.
A.M. is a 10-year-old boy of Ashkenazi Jewish ancestry first
noted to have splenomegaly at age 2. Bone marrow examination
Table 2. Pretreatment and Posttreatment Pulmonary Function Study
Patient S.W.
Vital capacity
FEVl (FEVl/FVC%)
Thoracic gas volume
Steady-state diffusing
capacity
S,O,-rest-0, at 2U
min
S,O,-rest-0, at 2U
min
S,O,-exercise-0, at
4Umin
Patient G.S.
Vital capacity
FEVl (FEVl/FVC%)
Thoracic gas volume
Steady-state diffusing
capacity
P,O, mmHg-rest
S,O,-walking 4 mph
6% grade
Pretreatment
9 mo Treatment 11 mo Treatment
(% of predicted) (%of predicted) 1% of predicted)
2.54 (74)
1.83(72)
2.02 (78)
2.56 (75)
1.89 (67)
2.18 (84)
2.72 (79)
1.91 (67)
2.29 (89)
5.9 (30)
6.6 (36)
5.5 (29)
72-79
82-86
78-81
82-88
89-92
88-92
47-55
62-67
58-67
revealed the diagnosis of Gaucher disease. He did well until age 8,
at which time increased bleeding at tonsillectomy required transfusion of platelets, plasma, and packed red blood cells. Because of
continued episodes of epistaxis, modest thrombocytopenia, and
massive splenomegaly, a partial splenectomy was performed. Since
this time the patient has had repeated episodes of fever and bone
pain. His height has been below the 10th percentile for his age.
Modest hepatomegaly and enlargement of the residual spleen was
evident on physical examination and confirmed by imaging. Pertinent clinical and laboratory findings at the time enzyme therapy
was started in September 1990 are summarized in Table 1.
B.F. is a 39-year-old Jewish man known to have Gaucher disease
since he was 4 or 5 years of age. The diagnosis was originally
established because two older siblings also had Gaucher disease,
and he had only minimal symptoms until he was about 30 years old.
5 mo treatment
3.66(103)
2.17 (76)
2.86 (90)
4.03 (114)
2.29 (80)
2.72 (85)
..
7.1 (43)
60
8.6 (54)
69
91.5
93.9
0
40
80
120
160
Time (minutes)
Fig 1. Clearance of glucocerebrosidase activity from plasma after
conclusion of a 2-hour infusion. The T,,, is calculated to be 11 minutes.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ENZYME REPLACEMENT IN GAUCHER DISEASE
1185
Fig 2. The effect of treatment
with mannose terminated glucocerebrosidase on the hemoglobin level and platelet count of
four patients. Patient S.W. did
not receive enzyme between
days 179 and 243 of the study.
His main symptoms in recent years had been related to massive
hepatosplenomegaly,marked pancytopenia,and compression fractures of the thoracic spine. Although splenectomy had been
repeatedly recommended to him over the past several years he had
declined. In recent months he had several splenic infarcts and his
blood hemoglobin concentration had decreased to as low as 5 g%.
Detailed findings at the time that treatment was initiated are
presented in Table 1.
Laboratory studies. The angiotensin converting enzyme (ACE)
activity of serum was measured on samples that had been stored at
-20°C. All samples from each patient were assayed simultaneously
using hippuryl-L-histidyl-L-leucineas substrate.” Plasma p-glucosidase activity was measured at pH 4.0 using 4-methyl umbelliferyl-Bglucoside as substrate.% Other clinical laboratory studies were
performed by standard methods.
Measurement of liver and spleen volume. Axial l-cm contiguous
slices through the liver were acquired using T1 weighted imaging
parameters on a 1.5 Tesla GE MRI Scanner (General Electric,
Milwaukee, WI). The liver and spleen contours were outlined on
each slice with the area calculated by computer. The areas for each
slice were then scanned to yield the total volume in cubic
centimeters. The ultrasound measurements were obtained using a
B-mode scanner (Picker International, Highland Heights, OH)
selecting the longest dimensions in the transverse, anteriorposterior (AP), and longitudinal directions. An ultrasound size
index was computed as the product of these dimensions.
Pulmonary function. The arterial oxygen saturations (S,O,)
were measured using a Hewlett-Packard ear oximeter (model
47201A). S.W.was continuously on nasal oxygen at 2 to 4 Umin.
The reported value for S,O, was that at which she stabilized after 5
minutes at rest or 2 minutes of exercise walking on the treadmill at
0.7 mph. The pretreatment values represented the range on four
studies, one before treatment and the other three during the first
month of treatment. The posttreatment values are the range of two
tests done during the 9th month and one test done during the 11th
month.
The exercise S,O, of G.S. was recorded during a staged exercise
test with the work rate increasing each minute. The S,02 was
averaged each breath for the last 30 seconds of the stage. The
values given are for walking at 4 mph at 6% grade, the highest stage
completed on both pretreatment and posttreatment tests. Posttreatment studies were performed in the fifth month of therapy.
Enzyme administrution. Mannose terminated glucocerebrosidase (Ceredase) was purchased from Genzyme. The preparation
was infused intravenously over a 2-hour period. All patients were
given the same total dose of enzyme, viz, 30 U of enzyme per month
per kilogram of body weight. The dosage was fractionated so that
the enzyme was administered every other day or three times a
week, except that patient S.W.was given enzyme only twice a week
for the first 14 doses because more frequent administrationwas not
Fig 3. Patient S.W. liver function tests. The administration of
mannose terminated glucocerebrosidase is denoted by the hatched
bars. Results are presented as the percentage of the upper limit of
normal for each test. Two transient episodes occurred during which
there was a marked increase in transaminase levels. These were
associated with abdominal pain and may have represented liver
infarctions. Apart from these episodesthere was steady improvement
SGOT; (+),
SGPT;
of liver function tests toward normal. (+),
( 4 - 1 , y = GT; (C),
alkaline phosphatase.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1186
BEUTLER ET AL
allowed under the then Food and Drug Administration-approved
protocol.
All patients except S.W. received enzyme therapy without
interruption. Therapy of this patient was interrupted after 6
months. She was observed closely for 2 months to determine
whether disease manifestations would recur rapidly. Through a
misunderstanding S.W. was given a single dose of 30 Ukg body
weight on day 243 of the study by another physician not connected
with this study.
RESULTS
Clearance of enzymefromplasma. Blood anticoagulated
in EDTA was drawn from B.F. before enzyme infusion, at
the end of a 2-hour infusion of 2.3 U Ceredasekg body
weight, and at 10- or 11-minute intervals immediately
following the infusion. The levels are shown in Fig 1. The
calculated one-half time was 11minutes.
Adverse effects. No adverse effects of enzyme infusion
were noted in any patient.
Hematologic effects. The effect of treatment on the
hemoglobin levels and the platelet counts of the patients is
shown in Fig 2. In the case of patients S.W., A.M., and B.F.,
an initial decrease in the hemoglobin level was observed.
This decrease may have been of iatrogenic origin, at least in
part, because of the frequent blood tests required by the
protocol during the first week of treatment. Subsequently
all patients showed an increase in the hemoglobin, with
normalization of counts in the case of S.W. and A.M., who
were anemic at the beginning of the study.
The platelet counts of all of the patients also increased.
At the beginning of treatment the platelet count of S.W.
was near the lower limit of normal, and it progressively
increased during treatment. G.S. was mildly thrombocytopenic, and her platelet counts rapidly returned to the
normal range.
Liverfunction and liver and spleen size. Patient S.W. had
markedly abnormal liver function tests at the outset of the
study and these showed rapid deterioration during the first
month of treatment. Subsequently, as shown in Fig 3, her
liver function tests all improved except for a transient
elevation of transaminase values during the fourth month,
possibly as a result of a hepatic infarction. The other three
patients had no major liver function abnormalities, and the
results of liver function tests remained normal during the
course of the study.
S.W. and G.S. manifested marked hepatomegaly and this
regressed during treatment, as shown in Figs 4 and 5. The
liver and spleen size of A.M. had each decreased 10% after
6 months of treatment. Quite remarkably the child had
gained 2.9 kg or 10% in body weight during this time. He
had grown 7 cm. The ultrasound size index of the liver of
B.F. had decreased a remarkable 22% after only 2 months
of treatment. The maximum length of his spleen had
decreased from 34.7 to 23.4 cm and the maximum anteriorposterior diameter from 23.5 to 20.4 cm.
Angiotensin converting enzyme. The level of angiotensin
converting enzyme was greatly increased in all patients, as is
characteristic of Gaucher disease?l It tended to decrease
during treatment (Fig 6), except for patient B.F., whose
follow-up was only 1month.
Skeletal changes. The major skeletal manifestations of
Gaucher disease (marrow infarction and endoskeletal expansion) did not change in radiographic appearance with
treatment in any of the patients. Patient S.W. continued to
have fleeting bone pains and A.M., who had been subject to
sporadic episodes of severe bone pain, suffered one episode
of moderate pain after about 4 months of treatment.
Pulmonaiy function. Modest improvement of pulmonary function was documented in patients S.W. and G.S.,
who had impaired lung function at the beginning of
treatment. The results of these studies are summarized in
Table 2.
Subjective symptoms. All four patients experienced subjective improvement during the course of treatment. S.W.
was able to resume limited activities, driving an automobile,
and engaging in handicraft hobbies and some social activities. She had been unable to engage in any of these
activities for a year or so before beginning enzyme therapy.
-100
0
100
200
300
400
500
Day of Treatment
8
U
C
-
tS.W.
14000 12000 -10000 -8000 --
GS.
A
t
A
6000
-2500 -2000 -1500 -1000 -500
0
500
Day of Treatment
Fig 4. The effect of treatment with glucocerebrosidaseon the liver
volume of patients S.W. and G.S. The upper panel depicts quantitative measurement of liver volume by magnetic resonance imaging;
the lower panel an empiric volume index, calculated by multiplying
the three maximum dimension obtained on ultrasound imaging (see
text). The latter index was measured on both patients for a period of
over 5 years before the initiation of enzyme therapy, using the same
equipment throughout. It is apparent that both patients had a
gradually increasing volume index followed by an abrupt decrease
after institutionof therapy.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ENZYME REPLACEMENT IN GAUCHER DISEASE
Fig 5. (A) Transverse magnetic resonance imaging (MRI)
scan through mid-abdomen of
G.S. before start of treatment.
(B) MRI scan through approximately the same level after 4
months of treatment. Arrows
show the liver edge. K, kidney;
RL, right lobe of liver; LL, left
lobe of liver.
1187
1
The frequency and severity of episodes of bone pain
diminished. G.S. no longer had appreciable shortness of
breath and felt stronger. A.M. had an improved appetite,
became more active, and began to gain weight rapidly. Bone
pains occurred less frequently. B.F. felt a marked increase
in well being as his hemoglobin increased from 5 g% to over
7 g%. He has resumed his teaching responsibilities as a
chemistry professor and no longer requires afternoon naps.
His appetite and meal portions have increased as his
organomegaly has decreased.
DISCUSSION
In the 1970s several groups of investigator^^'**^ attempted
to treat patients with Gaucher disease by administering
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1188
BEUTLER ET AL
Fig 6. The serum angiotensin converting enzyme
activity of the four patients treated with mannose
terminated glucocerebrosidase. All patients had a
marked increase in the activity of this enzyme, as we
have reported previously." and although there was
considerable variation, there was a tendency for the
enzyme activity to decrease during treatment.
purified placental glucocerebrosidase. We treated seven
patients with enzyme purified in our own laboratory with
total doses per patient of 2.2 U to 122 U,u corresponding in
catalytic activity of to about 3 U to 200 U of Ceredase.
Enzyme was either infused directly intravenously or was
encapsulated in eqthrocytes that were coated with Ig to
deliver them more effectively to the macrophage-monocyte
system. The patient receiving the largest dose was treated
over the course of a year. She weighed about 45 kg, and
therefore received only about 4 Ukg over the entire year, a
little more than 1%of the dose used in the present study.
Thus, it is not surprising that the clinical responses of our
patients were disappointing, although possible decrease in
the size of the liver of one of our patients was documented?
The dose of enzyme administered by Brady et al in their
studies of enzyme replacement was somewhat larger, and
there appeared to be some decrease in the amount of
glucocerebrosidein the liver. However, no objective clinical
response was demonstrated?323'26
Recent preliminary reports of the results of treatment of
Gaucher disease with mannose terminated glucocerebrosidase have been much more encouraging. Not only is the
amount of enzyme available for administrationmuch greater,
but the exposed mannose of Ceredase may serve to target it
more efficiently to the macrophage-monocyte system.'0.'l
Barton et al have presented a detailed account of a child
with moderately severe Gaucher disease treated with Ceredase over a 2-year period" and preliminary data on 12
patients treated for a year." The minimum amount of
enzyme administered by Barton et al was 60 Ukg body
weight each 2 weeks. At the price of $3.50 per unit the cost
of treating a 70-kg patient is approximately $382,000 per
year for enzyme alone.
Enzyme administered intravenously is very rapidly
cleared. We had earlier documented a TI, of placental
enzyme of about 30 minutes?* and the rate of clearance of
the modified enzyme was even more rapid. The mannose
receptors of macrophages have been studied extensively,2'"
but their density and the rate of which they turn over is not
precisely known. Moreover, it is entirely possible that the
sensitivity of cells of the macrophage-monocyte system to
the therapeutic effect of enzyme may vary during maturation of the monocyte to the Gaucher cell. Thus, the
injection of an enzyme bolus every 2 weeks could be a very
inefficient way to administer this very expensive product.
The present study was undertaken to determine whether a
much smaller, and thus much less costly, amount of enzyme
would exert a significant clinical effect if the enzyme was
administered at more frequent intervals. Because there is
marked heterogeneity in the clinical expression of Gaucher
disease and only scant published data about the results of
the much larger doses that have been used heretofore,
quantitative comparison of results is not feasible. However,
it seems apparent that patients with Gaucher disease
respond very well to the much smaller dose of Ceredase
that we have used, and the response observed seems, if
anything, more rapid than that described with much larger
total doses administered at infrequent intervals. We were
able to document decrease in organomegaly in all patients
and improvement in blood counts in those instances in
which anemia or thrombocytopenia was present. Over the
relatively short period encompassed by these studies no
objective changes in skeletal manifestations were observed,
although bone pain decreased. Longer-term administration
of enzyme appears to improve the x-ray appearance of the
skeletal lesions.'* The relatively slow response of skeletal
lesions is probably a reflection of the rate at which bone is
remodeled.
Future investigations will deal with the effect of the
enzyme when given by continuous infusion by portable
pump or frequent self administration. It is hoped the
effectiveness of even smaller doses of the enzyme will place
it within the reach of more patients with severe and
moderately severe Gaucher disease.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
ENZYME REPLACEMENT IN GAUCHER DISEASE
1189
REFERENCES
1. RingdCn 0, Groth C-G, Erikson A, Backman L, Granqvist S,
Mansson J-E, Svennerholm L Long-term follow-up of the first
successfulbone marrow transplantation in Gaucher disease. Transplantation 4666,1988
2. Rappeport JM, Ginns EI: Bone-marrow transplantation in
severe Gaucher disease. N Engl J Med 311:84,1984
3. Hobbs JR, Shaw PJ, Jones KH, Lindsay I, Hancock M:
Beneficial effect of pre-transplant splenectomy on displacement
bone marrow transplantation for Gaucher’s syndrome. Lancet
1:1111, 1987
4. De Duve C From cytases to lysosomes. Fed Proc 23:1045,
1964
5. Brady RO, Pentchev PG, Gal AE, Hibbert SR, Dekaban AS:
Replacement therapy for inherited enzyme deficiency. Use of
purified glucocerebrosidase in Gaucher’s disease. N Engl J Med
291:989,1974
6. Brady RO, Gal AE, Pentchev PG: Evolution of enzyme
replacement therapy for lipid storage diseases. Life Sci 71235,
1974
7. Beutler E, Dale GL: Enzyme replacement therapy, in Atkinson D, Fox CF (eds): Covalent and Non-covalent Modulation of
Protein Function. San Diego, CA, Academic, 1979, p 449
8. Beutler E, Dale GL, Guinto E, Kuhl W: Enzyme replacement
therapy in Gaucher’s disease: Preliminary clinical trial of a new
enzyme preparation. Proc Natl Acad Sci USA 744620,1977
9. Belchetz PE, Crawley JCW, Braidman IP, Gregoriadis G
Treatment of Gaucher’s diseasewith liposome-entrappedglucocerebroside: beta-glucosidase. Lancet 2116,1977
10. Achord DT, Brot FE, Bell CE, Sly WS: Human betaglucuronidase:In vivo clearance and in vitro uptake by a glycoprotein recognition system on reticuloendothelial cells. Cell 15969,
1978
11. Doebber TW, Wu MS, Bugianesi RL, Ponpipom MM,
Furbish FS, Barranger JA, Brady RO, Shen Ty: Enhanced
macrophage uptake of synthetically glycosylated human placental
beta-glucocerebrosidase.J Biol Chem 2572193,1982
12. Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO:
Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA
871912,1990
13. Barton NW, Brady RO, Doppelt SH, Mankin HJ, DiBisceglie AM, Hill SC, Verderese CL, Graham OC, Argoff CE, Grewal
RP, Yu K-T Clinical effectiveness of enzyme replacement in
Gaucher’s disease. Clin Res 38:457A, 1990 (abstr)
14. Beutler E, Saven A, Gamer P, Dawson A: Enzyme replacement therapy in Gaucher disease. Blood 76:177a, 1990 (abstr,
SUPPl)
15. Beutler E, Kuhl W. Detection of the defect of Gaucher’s
disease and its carrier state in peripheral-blood leukocytes. Lancet
1:612,1970
16. Beutler E, Kuhl W: The diagnosis of the adult type of
Gaucher’s disease and its carrier state by demonstration of
deficiency of beta-glucosidase activity in peripheral blood leukocytes. J Lab Clin Med 76:747,1970
17. Beutler E, Kuhl W p-Glucosidase.Chapter A32, in Williams
WJ, Beutler E, Erslev AJ, Lichtman MA (eds): Hematology. New
York, NY, McGraw-Hill, 1990, p 1762
18. Zimran A, Sorge J, Gross E, Kubitz M, West C, Beutler E:
Prediction of severity of Gaucher’n disease by identification of
mutations at DNA level. Lancet 2:349,1989
19. Beutler E, West C Sex-related differences in activity of
angiotensin converting enzyme in serum. Clin Chem 29:1570,1983
20. Raghavan SS, Topol J, Kolodny EH: Leukocyte betaglucosidase in homozygotes and heterozygotes for Gaucher disease. Am J Hum Genet 32158,1980
21. Lieberman J, Beutler E Elevation of serum angiotensinconverting enzyme in Gaucher’s disease. N Engl J Med 2941442,
1976
22. Beutler E, Dale GL, Kuhl W Replacement therapy in
Gaucher’s disease, in Desnick RJ (ed): Enzyme Therapy in
Genetic Diseases: 2. New York, NY, Liss, 1980, p 369
23. Brady RO, Barranger JA, Furbish FS, Stowens DW, Ginns
EI: Prospects for enzyme replacement therapy in Gaucher disease,
in Desnick RJ, Gatt S, Grabowski GA (eds): Gaucher Disease: A
Century of Delineation and Research. New York, NY, Liss, 1982, p
669
24. Brady RO, Pentchev PG, Gal AE: Investigations in enzyme
replacement therapy in lipid storage diseases. Fed Proc 34:1310,
1975
25. Pentchev PG, Brady RO, Gal AE, Hibbert SR: Replacement
therapy for inherited enzyme deficiency. Sustained clearance of
accumulated glucocerebrosidein Gaucher’s disease following infusion of purified glucocerebrosidase.J Mol Med 1:73,1975
26. Brady RO, Barranger JA, Gal AE, Pentchev PG, Furbish
FS: Status of enzyme replacement therapy for Gaucher disease, in
Desnick RJ (ed): Enzyme Therapy in Genetic Diseases: 2. New
York, NY, Liss, 1980, p 361
27. Lennartz MR, Cole FS, Stahl PD: Biosynthesis and processing of the mannose receptor in human macrophages. J Biol Chem
264:2385,1989
28. Lennartz MR, Cole FS, Shepherd VL,Wileman TE, Stahl
PD: Isolation and characterization of a mannose-specificendocytosis receptor from human placenta. J Biol Chem 262:9942,1987
29. Clohisy DR, Chappel JC, Teitelbaum SL: Bone marrowderived mononuclear phagocytes autoregulate mannose receptor
expression. J Biol Chem 2645370,1989
30. Lennartz MR, Wileman TE, Stahl PD: Isolation and characterization of a mannose-specific endocytosis receptor from rabbit
alveolar macrophages. Biochem J 245705,1987
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1991 78: 1183-1189
Enzyme replacement therapy for Gaucher disease
E Beutler, A Kay, A Saven, P Garver, D Thurston, A Dawson and B Rosenbloom
Updated information and services can be found at:
http://www.bloodjournal.org/content/78/5/1183.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.