Tài liệu Gaucher disease: pathological mechanisms and modern management ppt

review

Gaucher disease: pathological mechanisms and modern
management
Marina Jmoudiak and Anthony H. Futerman
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel

Summary
Gaucher disease, the most common lysosomal storage disorder, is caused by the defective activity of the lysosomal enzyme,
acid-b-glucosidase (GlcCerase), leading to accumulation of
glucosylceramide (GlcCer), particularly in cells of the macrophage lineage. Nearly 200 mutations in GlcCerase have been
described, but for the most part, genotype-phenotype correlations are weak, and little is known about the down-stream
biochemical changes that occur upon GlcCer accumulation
that result in cell and tissue dysfunction. In contrast, the
clinical course of Gaucher disease has been well described, and
at least one treatment is available, namely enzyme replacement
therapy. One other treatment, substrate reduction therapy, has
recently been marketed, and others are in early stages of
development. This review, after discussing pathological mechanisms, evaluates the advantages and disadvantages of existing
therapies.
Keywords: Gaucher disease, lysosomal storage disease, glucocerebrosidase, enzyme replacement therapy, macrophage.
Gaucher disease (GD) is a lysosomal storage disorder (LSD).
These metabolic disorders are caused by mutations in genes
encoding a single lysosomal enzyme or cofactor, resulting in
intracellular accumulation of undegraded substrates (Neufeld,
1991; Futerman & van Meer, 2004). Most LSDs, including GD,
are inherited in an autosomal recessive fashion. In GD, 200
different mutations have been described in the gene encoding
lysosomal glucocerebrosidase (glucosylceramidase, GlcCerase)
(Beutler & Grabowski, 2001), and as a result, glucosylceramide
(GlcCer, glucosylcerebroside) is degraded much more slowly

than in normal cells and accumulates intracellularly, primarily
in cells of mononuclear phagocyte origin. These GlcCer-laden
macrophages are known as ‘Gaucher cells’, and are the classical
hallmark of the disease. Since GlcCer is an important
constituent of biological membranes and is a key intermediate
in the biosynthetic and degradative pathways of complex

Correspondence: A.H. Futerman, Department of Biological Chemistry,
Weizmann Institute of Science, Rehovot 76100, Israel.

glycosphingolipids (Fig 1), its accumulation in GD is likely to
have severe pathological consequences.
Historically, and from the clinical point of view, GD has
been divided into three major subtypes, namely types 1, 2
and 3, although a recent trend is to consider GD as a
continuum of disease states (Goker-Alpan et al, 2003). Type
1 is the most common form of GD and is essentially a
macrophage disorder, lacking primary central nervous system involvement. Patients with type 1 GD display a large
variety of symptoms, ranging from patients who are entirely
asymptomatic to those that display child-onset disease.
Clinical manifestations normally begin with splenomegaly
and hepatomegaly, anaemia and thrombocytopenia. Bone
manifestations include osteopenia, lytic lesions, pathological
fractures, chronic bone pain, acute episodes of excruciating
bone crisis, bone infarcts, osteonecrosis and skeletal deformities (Zimran, 1997). Lung involvement includes interstitial
lung disease (Zimran, 1997) and pulmonary hypertension
has also been reported in a small number of patients with
type 1 GD (Elstein et al, 1998). Type 2 GD (Beutler &
Grabowski, 2001), the acute neuronopathic form, is
characterized by neurological impairment in addition to

visceral symptoms. The neurological symptoms start with
oculomotor abnormalities followed by brainstem involvement, and these patients usually die within the first
2–3 years of life. Type 3 GD is also characterized by
neurological involvement but neurological symptoms generally appear later in life than in type 2 disease, and include
abnormal eye movements, ataxia, seizures, and dementia,
with patients surviving until their third or fourth decade
(Erikson et al, 1997). Recently, a clinical association has
been reported between the presence of mutations in the
GlcCerase gene and Parkinsonism (Aharon-Peretz et al,
2004; Lwin et al, 2004).
Although it is generally assumed that the severity of GD
depends on levels of residual GlcCerase activity (Beutler &
Grabowski, 2001), this has been difficult to prove for most
mutations (Meivar-Levy et al, 1994). Likewise, genotypephenotype correlations are poor, although certain mutations
are known to predispose to certain disease types. Thus,
homozygosity for L444P normally results in neuronopathic
disease whereas the presence of even one mutant allele for

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doi:10.1111/j.1365-2141.2004.05351.x

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Sphinganine
Dihydroceramide
synthase
Sphingomyelin

Dihydroceramide
Dihydroceramide
desaturase

Fig 1. Metabolic relationships of GlcCer. GlcCer is formed from ceramide by the action of
glucosylceramide synthase. Its degradation, by
GlcCerase, is defective in GD. GlcCer is the
precursor of a number of complex glycosphingolipids, whose defective degradation leads
to other LSDs (Futerman & van Meer, 2004).
Enzymes of the biosynthetic pathway are shown
in italics, and degradative enzymes with the
associated disease, in bold.

N370S normally prevents neurological involvement. Remarkably, phenotype severity may vary even among siblings or in
identical twins (Lachmann et al, 2004).
In this review, we will first discuss the secondary biochemical pathways that may be involved in development of disease
pathology (Futerman & van Meer, 2004), and then discuss
disease management and possible new therapeutic options, a
number of which have been proposed over the past few years.

Pathological mechanisms
Glucosylceramide accumulation
GlcCer was first characterized as the accumulating lipid in GD
in 1934 (Aghion, 1934) and is now known to accumulate in
essentially every tissue where its levels have been measured. By
way of example, GlcCer accumulates to levels of 30–40
mmol/kg tissue in spleen obtained from all three types of GD,
and glucosylsphingosine (GlcSph), the deacylated form of
GlcCer, which is usually not detectable in normal tissues,
accumulates to lower but significant levels of 0Ỉ1–0Ỉ2 mmol/

kg (Nilsson et al, 1982a). Interestingly, GlcSph is found at
higher levels in the brains of type 2 and 3 patients with GD
(Orvisky et al, 2002) suggesting a potential pathological role
for this lipid in types 2 and 3 GD (Suzuki, 1998). The fatty acid
composition of GlcCer differs between the brain and peripheral systems, with a prevalence of stearic acid in the central
nervous system and palmitic acid in GlcCer of peripheral
tissues, implying a different metabolic or cellular origin of
GlcCer in different tissues (Gornati et al, 2002). GlcCer levels
are also elevated in the plasma of patients with GD (Nilsson

e
as )
lin
ye k A/B
om ic
ing -P
ph ann
S m
e
(Ni

SM

Galactosyl- Ga/Cersythase
Ceramide
ceramide
β-galactosidase
(Krabbe disease)
GlcCer
synthase

e

s
tha

syn

Cera
(Farb midase
er dis
ease)
Glucosylceramidase
(Gaucher disease)

Sphingosine

Glucosylceramide

Lactosylceramide

Complex glycosphingolipids

et al, 1982b; Gornati et al, 1998). Finally, changes in the levels
of other glycosphingolipids have also been reported in some
cases of GD, but there is no clear consensus about the extent or
significance of these changes.
Despite the elevated levels of GlcCer in GD tissues, it
appears that GlcCer levels are nevertheless not sufficiently high
enough to account for changes in tissue mass and/or tissue

pathology. Thus, whereas the size of the spleen increases up to
25-fold in patients with GD, GlcCer accounts for <2% of the
additional tissue mass (Cox, 2001), implying that although
GlcCer accumulates significantly in GD, other biochemical
pathways must be activated in GD and contribute to changes
in tissue mass and development of pathology.
Residual levels of GlcCerase in patients with GD have been
variously estimated at 5–25% of normal activity, depending on
the substrate used and the conditions of the reaction [see, for
instance (Svennerholm et al, 1980, 1986; Sa Miranda et al,
1990; Meivar-Levy et al, 1994; Rudensky et al, 2003)]. Most of
the 200 known GlcCerase mutations partially or entirely
decrease catalytic activity or are believed to reduce GlcCerase
stability (Grace et al, 1994). The most common mutation,
N370S, accounts for 70% of mutant alleles in Ashkenazi Jews
and 25% in non-Jewish patients (Beutler & Grabowski, 2001).
N370S predisposes to type 1 disease and precludes neurological
involvement, suggesting that it causes relatively minor changes
in GlcCerase structure and hence catalytic activity.
Recently, the 3D-structure of GlcCerase was determined
(Dvir et al, 2003). The structure comprises three non-contiguous domains. Domain 1 consists of one major threestranded anti-parallel b-sheet flanked by a perpendicular
N-terminal strand and loop. Domain II consists of two

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Review
closely-associated b-sheets that form an independent domain

resembling an immunoglobulin fold. Domain III is a (b/a)8
barrel containing the catalytic site. The function of the two
non-catalytic domains is unknown, but the location of
mutations throughout all three domains suggests they play
important regulatory roles. No clear correlation is apparent
between the spatial location of particular mutants and the
severity of clinical symptoms.
In rare cases, GD can be caused by mutations in the saposin
C domain of the prosaposin gene (Horowitz & Zimran, 1994),
which encodes the saposin C activator protein that is required
for optimal GlcCerase activity (Zhao & Grabowski, 2002).
Recently, the crystal structure of a related saposin, saposin B,
was determined (Ham, 2003), but the structure of saposin C,
and its mode of interaction with GlcCerase are not known
(Vaccaro et al, 1999). Determining how saposin C regulates
GlcCerase activity will be important for understanding how
GlcCerase activity is regulated in vivo.

Cellular pathology
The cellular pathology of GD begins in lysosomes, membranebound organelles that consist of a limiting, external membrane
and intra-lysosomal vesicles. Endogenous and exogenous
macromolecules, including GlcCer, are delivered to lysosomes
by processes such as endocytosis, pinocytosis, phagocytosis and
autophagocytosis (Sabatini & Adesnik, 2001) and the lysosomal proteins themselves, at least the soluble hydrolases, are
targeted to lysosomes mainly via the mannose-6-phosphate
receptor (Aerts et al, 2003). Surprisingly, the mechanism by
which GlcCerase is targeted from its site of synthesis in the
endoplasmic reticulum to lysosomes is not known (Rijnboutt
et al, 1991).
In addition, little is known about how GlcCer accumulation

in lysosomes leads to cellular pathology. One vital, but as yet
unanswered question, is whether GlcCer mediates all of its
pathological effects from within the lysosome, or whether
some GlcCer can escape the lysosome and thereby interact with
biochemical and cellular pathways located in other organelles.
Some evidence exists to support the latter possibility. Thus,
recent studies, mainly from our laboratory, have shown
changes in phospholipid metabolism in neuronal models of
GD (Bodennec et al, 2002) and in a chemically-induced
macrophage model (Trajkovic-Bodennec et al, 2004), changes
in calcium homeostasis in a GD neuronal model (Korkotian
et al, 1999; Lloyd-Evans et al, 2003) and in brains obtained
post-mortem from patients with type 2 GD (Pelled et al,
2004). Since phospholipid metabolism and calcium homeostasis are regulated in the endoplasmic reticulum, this implies
that GlcCer might be able to escape lysosomes, at least upon its
accumulation in GD. Interestingly, a recent study has shown a
functional and morphological connection between lysosomes
and the sarcoplasmic reticulum, which is involved in calcium
homeostasis in myocytes (Kinnear et al, 2004). Other studies
have suggested unexpected locations for glycosphingolipids
180

[reviewed in (Ginzburg et al, 2004)], including a recent study
showing the accumulation of ganglioside GM1 in the endoplasmic reticulum in a model of GM1 gangliosidosis (Tessitore
et al, 2004).
Subsequent to GlcCer accumulation in lysosomes, or its
escape from lysosomes, GlcCer causes many cellular responses,
particularly in Gaucher cells, macrophages that actively
phagocytose other cells, especially senescent blood cells, from
the circulation (Pennelli et al, 1969; Naito et al, 1988; Bitton

et al, 2004). The macrophage origin of Gaucher cells has been
demonstrated in many studies, including the demonstration of
pre-Gaucher monocytes and monocytoid cells with characteristic cytoplasmic inclusions (Parkin & Brunning, 1982), the
detection of surface macrophage markers (Florena et al, 1996;
Boven et al, 2004), and intense phagocytic activity (Pennelli
et al, 1969). Gaucher cells are about 20–100 lm in diameter,
and have small, usually eccentrically placed nuclei and
cytoplasm with characteristic crinkles or striations. Moreover,
all cells of the mononuclear phagocyte system, and especially
tissue macrophages of the liver (Kupffer cells), bone (osteoclasts), the central nervous system (microglia, cerebrospinal
fluid macrophages), lungs (alveolar macrophages), spleen,
lymph nodes, bone marrow, gastro-intestinal and genitourinary tracts, pleura, peritoneum, and others, can be affected
in GD (Zimran, 1997). Interestingly, Gaucher-like cells are well
described in various haematological malignancies unrelated to
GD, including Hodgkin’s disease, non-Hodgkin’s lymphoma,
multiple myeloma (MM) and chronic myeloid leukaemia
(CML) (Zimran, 1997), and occasionally reported in thalassaemia (Hakozaki et al, 1979).
Since macrophages are the main cell type affected in GD,
some effort has been invested to determine how and why
macrophage biology is altered in GD. It is now apparent that
the pathology is caused not just by the burden of storage
material, but by macrophage activation. Thus, levels of
interleukin-1b (IL-1b), interleukin-1 receptor antagonist,
IL-6, tumour necrosis factor-a (TNFa), and soluble IL-2
receptor (sIL-2R) are elevated in the serum of Gaucher patients
(Barak et al, 1999), as are CD14 and M-CSF (Hollak et al,
1997a) (Table I). These changes could potentially explain some
of the pathological features, since IL-1b, TNFa, IL-6 and Il-10
may contribute to osteopenia, IL-1b, TNFa and IL-6 may
contribute to activation of coagulation and hypermetabolism,

IL-6 and IL-10 to gammopathies (Brautbar et al, 2004) and
MM (Barak et al, 1999). Changes in levels of other macrophage-derived markers have also been reported in the plasma of
GD (Table I). However, on macrophages themselves, expression of pro-inflammatory mediators is not always apparent
(Boven et al, 2004), although markers characteristic of alternatively activated macrophages are found. Finally, chitotriosidase, a human chitinase produced by activated macrophages,
is markedly elevated in Gaucher plasma and is commonly used
to examine GD severity and improvement upon treatment
(Hollak et al, 1994; Renkema et al, 1997). Other haematological manifestations unconnected to macrophages, such as

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Table I. Macrophage-derived molecules elevated in the plasma of GD patients.
Macrophage-associated molecule

Function

Reference

sCD14*
sCD163
CD36
CCL18
IL-1 receptor antagonist
sIL-2 receptor
IL-1b
IL-6
IL-8
IL-10
TNFa

M-CSF*
TGFb1*
Cathepsins B, K and S
Apolipoprotein E
Chitotriosidase

Monocyte/macrophage activation marker
Anti-inflammatory
Scavenger receptor
Alternative activated macrophage marker
Anti-inflammatory

Hollak et al (1997a)
Boven et al (2004); Moller et al (2004)
Boven et al (2004)
Boot et al (2004); Boven et al (2004)
Barak et al (1999); Boven et al (2004)
Barak et al (1999)
Barak et al (1999)
Allen et al (1997); Hollak et al (1997a); Barak et al (1999)
Hollak et al (1997a)
Allen et al (1997)
Hollak et al (1997a); Barak et al (1999)
Hollak et al (1997a)
Perez Calvo et al (2000)
Moran et al (2000)
Cenarro et al (1999)
Hollak et al (1994)

Pro-inflammatory

Pro-inflammatory/anti-inflammatory
Pro-inflammatory
Anti-inflammatory
Pro-inflammatory
Macrophage-derived cytokine
Anti-inflammatory
Cysteine proteinases
Produced by activated macrophages
Produced by activated macrophages

*s, soluble; M-CSF, macrophage colony-stimulating factor; TGFb1, transforming growth factor-b1.

decreased levels of coagulation factors (Hollak et al, 1997b;
Barone et al, 2000) and decreased platelet aggregation (Gillis
et al, 1999), have also been reported [reviewed in (Zimran,
1997; Beutler & Grabowski, 2001)].
In summary, the main unresolved mechanistic questions
concern how GlcCer accumulation leads to cellular pathology.
Specifically, it is not known if altered macrophage function is
responsible for all of the pathological manifestations in all
tissues where pathology is observed, or whether secondary
biochemical changes caused directly by GlcCer accumulation in
the specific tissues also play a role in pathological development.
For instance, in the central nervous system, there is evidence of
infiltrating macrophages (Wong et al, 2004), but neurons
themselves are also known to be defective, at least with respect
to calcium homeostasis (Pelled et al, 2004).

Disease management
Unlike in most other LSDs, type 1 GD patients are in the

relatively advantageous position of having at least one
commercially-available treatment option, namely enzyme
replacement therapy (ERT), that alleviates many disease
symptoms although not dealing with the underlying cause,
which would require gene therapy. In this section, we will
discuss ERT and other emerging treatment options.

Patient assessment
Since there is large variability in the extent of symptoms
displayed by patients with type 1 GD, the assessment of disease
development and progression is an essential feature of disease
management, and integral to the decision about whether a
patient is treated by ERT. Moreover, since ERT is prohibitively
expensive in some countries, decisions are sometimes also

based on economic as well as medical considerations (Beutler,
1994). In terms of medical considerations, a scoring index for
assessing the severity of type 1 GD has been proposed (Zimran
et al, 1989). It is also generally accepted that each patient
should be evaluated individually, when in general the presence
of complications, such as anaemia, bleeding tendency because
of thrombocytopenia, organomegaly, liver or pulmonary
function abnormality, or bone disease, are indications for
therapy. In paediatric cases, indirect manifestations, such as
malnutrition, growth retardation, impaired psychomotor
development or severe fatigue, are also important factors
(Charrow et al, 2004; Grabowski et al, 2004).
GD is normally diagnosed in symptomatic patients during
initial clinical examination, or by the presence of unexpected
anaemia, thrombocytopenia and organomegaly, or by histological analysis performed for an unrelated reason in patients

not suspected to have GD, or by genetic screening. Diagnosis is
confirmed by enzymatic assay and mutational analysis. The
subsequent work-up is directed towards assessment of disease
severity and prognosis, including determination of the presence of concomitant conditions that can be aggravated by GD,
or contraindications for treatment. A decision on the use of
appropriate therapy is made based on the whole clinical
picture. Treatment should be directed to symptom elimination, improvement of well-being, and prevention of irreversible damage (Pastores et al, 2004). The frequency of
re-evaluation depends on disease severity and should be
assessed on an individual basis (Weinreb et al, 2004).

Enzyme replacement therapy
The goal of all treatment strategies for GD is to reduce the
GlcCer storage burden, thus diminishing the deleterious effects
caused by its accumulation (see above). ERT achieves this by

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supplementing defective enzyme with active enzyme (Grabowski & Hopkin, 2003) using CerezymeÒ (Genzyme Corporation,
Cambridge, MA, USA), a recombinant form of GlcCerase
(Weinreb et al, 2002). ERT has proved to be safe and effective
over a period of >12 years. Indeed, the success story of ERT
should act as a stimulus for the development of ERT for other
LSDs (Desnick & Schuchman, 2002), and potentially for other
metabolic disorders caused by enzyme deficiencies. The history
of ERT has been extensively reviewed (see, for instance Brady,
1997, 2003, Desnick & Schuchman, 2002; Sly, 2004).

Vital to the success of ERT is the ability to target GlcCerase
to macrophages via the mannose receptor found at high levels
on the macrophage surface. Uptake of GlcCerase is achieved
with a high efficiency by remodelling its oligosaccharide chains
to expose core mannose residues, by sequential enzymatic
modification using sialidase, b-galactosidase and b-N-acetylglucosaminidase ( />cz_hc_aboutcz.asp). This modified enzyme is endocytosed
after it binds to cell-surface mannose receptors and is
subsequently delivered to lysosomes where it supplements
the defective enzyme (Grabowski & Hopkin, 2003). The
importance of uptake by mannose receptors is reinforced by
studies showing that up-regulation of the mannose receptor
can improve the delivery of recombinant b-glucosidase to
Gaucher macrophages (Zhu et al, 2003), and can, therefore,
improve the efficacy of ERT. However, a recent report has
suggested the absence of mannose receptors on splenic
Gaucher cells, but demonstrated their abundance on the
surrounding myeloid cells (Boven et al, 2004).
Reduction in organ volumes, improvement in haematological parameters, and amelioration of bone pain using ERT have
dramatically improved the quality of life for many patients with
GD (Charrow et al, 2000; Weinreb et al, 2002). Data collated in
the Gaucher Registry has summarized the effects of 2–5 years of
treatment on specific manifestations of type 1 GD. Anaemic
patients show an increase of haemoglobin concentrations to
normal or near normal levels within 6–12 months, with a
sustained response throughout 5 years. Thrombocytopenia in
patients with intact spleens responds most significantly during
the first 2 years, with slower improvement thereafter. In cases
of severe baseline thrombocytopenia, chances of achieving a
normal platelet count are lower. In splenectomised patients,
platelet counts normalize within 6–12 months. Hepatomegaly

and splenomegaly decrease by up to 60%, but spleen and liver
volumes nevertheless remain significantly above normal size.
Children receiving ERT also show improvement and the
prevention of development of complications that can otherwise
occur in later life, particularly skeletal abnormalities, even in
patients with severe underlying disease (Cohen et al, 1998;
Dweck et al, 2002). However, it should be noted that ERT is
essentially of no use for treating the neurological symptoms in
type 2 and 3 GD since it does not cross the blood–brain barrier
(Desnick & Schuchman, 2002), although visceral symptoms,
with the exception of lung involvement, are improved (Bove
et al, 1995; Altarescu et al, 2001).
182

Despite the notable success of ERT in treating patients with
type 1 GD, it would be lax of the medical and research
community to rest on their laurels and not to attempt to
improve ERT by the production of second generation enzymes.
For instance, although few systematic studies have been
published examining the fate of GlcCerase after infusion (the
main study was performed with CeredaseÒ (Genzyme,
Corporation), a first-generation, placental GlcCerase), it is
rapidly cleared from blood (within a few minutes), and has a
half-life in the bone marrow of only 14 h (Beutler &
Grabowski, 2001). Engineering a more stable enzyme, or an
enzyme with a higher catalytic activity, could reduce the
number of infusions and potentially also reduce cost, and the
recent availability of the 3D-structure of GlcCerase should help
in this regard (Dvir et al, 2003). Moreover, CerezymeÒ
generally has a poor effect on bones and lungs in patients

with pre-existing lesions, does not cross the blood–brain
barrier, and, of no less importance, is expensive and therefore
unavailable to patients in poor countries, imposing a disproportionate burden on the health care budget of a number of
countries with limited resources (Beutler, 1994). It should be
stressed that the GD market is relatively small in terms of
numbers of patients (about 3000 patients receive CerezymeÒ
world-wide), but it is our contention that basic research to
improve the efficacy of ERT, or to develop novel and
alternative treatments (see below) is essential to further
improve the quality of life of patients with type 1 GD.

Substrate reduction therapy
A new treatment has recently become available for type 1 GD,
namely substrate reduction therapy (SRT) using N-butyldeoxynojirimycin (NB-DNJ: ZavescaÒ; Actelion Pharmaceuticals,
Allschwill, Switzerland) (Lachmann, 2003). NB-DNJ is an
inhibitor of GlcCer synthase, the enzyme responsible for GlcCer
synthesis and hence synthesis of all GlcCer-based glycolipids
(Fig 1), and was originally shown to delay neurological
deterioration in Sandhoff mice (Platt et al, 1997), a model of
a GM2 gangliosidosis. Since GlcCer synthesis is reduced, levels
of its accumulation are lowered. A non-comparative phase I/II
study in adult patients with mild to moderate type 1 GD who
were unable or unwilling to receive ERT demonstrated the
clinical feasibility of SRT. Reductions in liver and spleen
volumes were observed, although haematological responses
were less impressive (Cox et al, 2000). Other clinical trials have
been, or are being performed with ZavescaÒ (Heitner et al,
2002; Zimran & Elstein, 2003), and a position statement on its
use in treating type 1 GD was recently published (Cox et al,
2003). Unlike CerezymeÒ, ZavescaÒ is given orally and does

cross the blood–brain barrier (Platt et al, 1997), and clinical
trials are currently also underway using ZavescaÒ for type 3 GD.
However, ZavescaÒ causes a number of side-effects (Futerman
et al, 2004), and therefore attempts are ongoing to develop
other GlcCer-synthase inhibitors for SRT (Abe et al, 2001).
Moreover, long-term reduction in glycolipid levels could

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Table II. Indications for choice of currently available GD treatments.
Enzyme replacement
therapy using CerezymeÒ

Substrate reduction
therapy using ZavescaÒ

First-line treatment for
Gaucher disease

Second treatment option
when ERT is unavailable
or unsuitable
Mild disease
Non-paediatric disease
Slower response option
Patient must use
contraceptives

Severe disease
Paediatric disease
Need for prompt response
Patients planning to have
children or unable/unwilling
to use contraceptives
Lack of improvement/side
effects with SRT treatment

Supplemental to ERT
in severe cases

affect a variety of cell functions because of the essential roles
that these lipids play in normal cell physiology (Buccoliero &
Futerman, 2003; Futerman & Hannun, 2004). Due to these
problems, ZavescaÒ has been approved in Europe (including
Israel) and in the USA only for patients for whom ERT is
‘unsuitable’ or ‘not a therapeutic option’ respectively (Table II).
Thus, ZavescaÒ is clearly not the last word in SRT.

Other management and treatment options
In addition to the treatments listed above, both of which are
directed at reducing GlcCer levels, a number of other management and treatment options are used either alone, or together
with ERT or SRT, to alleviate specific disease symptoms.
Bone disease. Bone disease usually designates the advanced
stages of GD, but susceptibility to fractures and avascular
necrosis can be the first sign of GD in otherwise asymptomatic
patients. Treatment of bone manifestations is mostly directed
at the prevention of irreversible complications, and ERT is
often of limited influence on bone density (Schiffmann et al,

2002). The use of biphosphonates, which act directly on
osteoclasts (Toyras et al, 2003), is an effective and safe means
to increase bone density and prevent complications (Samuel
et al, 1994; Wenstrup et al, 2004). Orthopaedic intervention
may be necessary in cases of pathologic fractures or avascular
necroses. Supportive management for bone pains or bone
crises may also be required.
Splenectomy. Once the most popular GD treatment, because of
the absence of other options, splenectomy is now performed
only in cases of severe thrombocytopenia or symptomatic
organomegaly that are unresponsive to ERT.
Bleeding tendency. As mentioned above, defective platelet
function, coagulation factor abnormalities and non-corrected
thrombocytopenia may cause increased bleeding risk in GD
patients, demanding appropriate evaluation and preparation
before surgical procedures.

Bone marrow replacement. Attempts to treat GD by bone
marrow transplantation (BMT) have been reported (Ringden
et al, 1995), and BMT has been shown to abolish
haematological and visceral disease (Tsai et al, 1992; Young
et al, 1997). In addition, some effect on limiting neurological
deterioration has been reported in type 3 GD (Krivit et al,
1999), but in general, BMT is not normally considered as a
realistic treatment for GD.
Pulmonary hypertension. Pulmonary evaluation should include
a Doppler echocardiogram to estimate right ventricular
systolic pressure (Weinreb et al, 2004). Risk factors for
severe, life-threatening pulmonary hypertension include
mutations other than N370S, a family history of pulmonary

hypertension, angiotensin converting enzyme I gene
polymorphism, asplenia and female sex (Mistry et al, 2002).
Neuronopathic GD management. A patient with GD and
neurological involvement is defined as having neuronopathic
disease, i.e. type 2 or 3. It has been suggested that these
patients, along with patients having mutations that are known
to predispose to neuronopathic disease, should undergo
thorough neurological evaluation and monitoring (Vellodi
et al, 2001). The best current treatment option is high-dose
ERT for visceral symptoms and supportive treatment for
neurological disease if required. Some of the new treatment
options, such as SRT, may eventually prove useful for treating
patients with type 2 and 3 GD.
Others. A clinical association has been reported between the
presence of mutations in the GlcCerase gene and Parkinsonism
(Aharon-Peretz et al, 2004; Lwin et al, 2004) but no
management options, apart from those routinely used for
Parkinsons disease, have yet been suggested. Likewise, patients
with haematological malignancies are normally referred to an
oncologist or haematologist.
Developing management and treatment options. The past few
years have seen a tremendous effort in the attempt to develop
new treatments for GD and other LSDs. Much of the impetus
for these advances is derived from the limitations of ERT, as
discussed above, and the lack of usefulness of ERT for LSDs in
which the brain is affected, but has also derived from renewed
interest in the structure, intracellular transport, stability and
activity of GlcCerase, and other lysosomal hydrolases affected
in other LSDs (Futerman & van Meer, 2004).

Chemical chaperones (enzyme enhancement therapy)
Amongst the potential exciting advances in GD treatment is
the recent proof of concept that chemical chaperones can be
used to stabilize or reactivate improperly-folded GlcCerase
(Fan, 2003; Desnick, 2004). Some GD mutations result in
improperly-folded GlcCerase that is retarded in the endoplasmic reticulum and degraded there, and chaperones, in

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183


Review
principle, enhance normal trafficking of the enzyme through
the secretory pathway, and thus increase its level in lysosomes.
Proof of principle was obtained by incubating cultured cells
expressing a mutant GlcCerase (N370S) with sub-optimal
concentrations of a GlcCerase inhibitor, N-nonyl-deoxynojirimycin, which resulted in elevated enzyme activity (Sawkar
et al, 2002). Likewise, incubation with N-octyl-b-valienamine,
another GlcCerase inhibitor, increased the protein level of a
mutant GlcCerase and up-regulated cellular enzyme activity
(Lin et al, 2004). Importantly, it should be emphasized that a
modest increase in GlcCerase activity should be sufficient to
achieve a therapeutic effect. Clearly, a substantial amount of
work is required before this approach will provide a therapeutic option for GD (e.g. optimization of inhibitor levels in
animal studies rather than in cultured cells, and determination
of efficacy in reducing GlcCer storage in the primary cell types
and tissues affected in GD), but this approach nevertheless
holds great promise for GD and other LSDs.

Gene therapy
Also holding great promise is gene therapy, which would of
course be the ultimate treatment for GD. However, it has been
largely unsuccessful to date in human patients, although
GlcCer storage can be significantly reduced in cultured cells by
gene transfer. For instance, recombinant adeno-associated viral
vectors containing human GlcCerase driven by the human
elongation factor 1-a promoter have recently been used and
shown to elevate GlcCerase levels in both normal and Gaucher
fibroblasts (Hong et al, 2004); moreover, intravenous administration of vectors to wild-type mice resulted in increased
GlcCerase activity that persisted for over 20 weeks. Other
vectors have been used (i.e. Kim et al, 2004, and reviewed in
Cabrera-Salazar et al, 2002), but the likelihood of gene therapy
becoming a viable option for GD in the near future in human
patients remains small. This is also true for other LSDs
(D’Azzo, 2003; Eto et al, 2004), and presents a major challenge
for the future.

Conclusion and future prospects
In this review, we have discussed the little that is known about
the pathological mechanisms leading from GlcCer accumulation in macrophages and other cells, to disease development.
The relative lack of knowledge is somewhat surprising, and
might be due, at least in part, to the availability of ERT, and
thus the feeling in the medical and research community that
there is little need to understand the basic mechanisms of
disease development and progression. However, a renewed
interest in GD, and in the biology of other LSDs, is apparent
from the recent scientific literature, and it is to be hoped that
the coming years will lead not only to new therapies based on
existing concepts, but new therapies based on an increased

understanding of the enzymology, cell biology, and the
pathophysiological mechanisms that underlie GD.
184

Acknowledgements
We thank Prof. Ari Zimran of the Gaucher Clinic, Sha’are
Zedek Hospital, Jerusalem, for helpful discussions. Anthony
H. Futerman is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science.

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