Futerman Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel Summary Gaucher disease, the most common lysosomal storage disor-der, is caused by the defecti
Trang 1Gaucher 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
disor-der, 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
macr-ophage lineage Nearly 200 mutations in GlcCerase have been
described, but for the most part, genotype-phenotype
corre-lations 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
mech-anisms, evaluates the advantages and disadvantages of existing
therapies
Keywords: Gaucher disease, lysosomal storage disease,
gluco-cerebrosidase, 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
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 sys-tem 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 deform-ities (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 involve-ment, 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 gener-ally 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, genotype-phenotype 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
Correspondence: A.H Futerman, Department of Biological Chemistry,
Weizmann Institute of Science, Rehovot 76100, Israel.
E-mail: tony.futerman@weizmann.ac.il
Trang 2N370S normally prevents neurological involvement
Remark-ably, phenotype severity may vary even among siblings or in
identical twins (Lachmann et al, 2004)
In this review, we will first discuss the secondary
biochemi-cal 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 of0Æ1–0Æ2 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
periph-eral 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
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-conti-guous domains Domain 1 consists of one major three-stranded anti-parallel b-sheet flanked by a perpendicular N-terminal strand and loop Domain II consists of two
Sphinganine
Sphingosine
Sphingomyelin Dihydroceramide
Dihydroceramide synthase
Dihydroceramide desaturase Ga/Cersythase
GlcCer synthase
SM synthase
Ceramide
Galactosyl-ceramide
ββ-galactosidase
(Krabbe disease)
Glucosylceramide
Lactosylceramide
Complex glycosphingolipids
Glucosylceramidase (Gaucher disease)
Ceramidase (Farbe
r disease)
Sphingomyelinase (Niemann-Pick A/B)
Fig 1 Metabolic relationships of GlcCer
Glc-Cer 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
glycosp-hingolipids, 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.
Trang 3closely-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,
membrane-bound 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
lysoso-mal 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
home-ostasis 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
[reviewed in (Ginzburg et al, 2004)], including a recent study showing the accumulation of ganglioside GM1 in the endo-plasmic 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 character-istic 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 (osteo-clasts), the central nervous system (microglia, cerebrospinal fluid macrophages), lungs (alveolar macrophages), spleen, lymph nodes, bone marrow, gastro-intestinal and genito-urinary 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 thalas-saemia (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 macroph-age-derived markers have also been reported in the plasma of
GD (Table I) However, on macrophages themselves, expres-sion of pro-inflammatory mediators is not always apparent (Boven et al, 2004), although markers characteristic of alter-natively activated macrophages are found Finally, chitotrios-idase, 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 haemato-logical manifestations unconnected to macrophages, such as
Trang 4decreased 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 histo-logical 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 pres-ence 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 elimin-ation, improvement of well-being, and prevention of irrever-sible 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
Table I Macrophage-derived molecules elevated in the plasma of GD patients.
sCD14* Monocyte/macrophage activation marker Hollak et al (1997a)
CCL18 Alternative activated macrophage marker Boot et al (2004); Boven et al (2004)
IL-1 receptor antagonist Anti-inflammatory Barak et al (1999); Boven et al (2004)
IL-6 Pro-inflammatory/anti-inflammatory Allen et al (1997); Hollak et al (1997a); Barak et al (1999)
Cathepsins B, K and S Cysteine proteinases Moran et al (2000)
Apolipoprotein E Produced by activated macrophages Cenarro et al (1999)
Chitotriosidase Produced by activated macrophages Hollak et al (1994)
*s, soluble; M-CSF, macrophage colony-stimulating factor; TGFb1, transforming growth factor-b1.
Trang 5supplementing defective enzyme with active enzyme
(Grabow-ski & Hopkin, 2003) using Cerezyme(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-acetyl-glucosaminidase (http://www.cerezyme.com/healthcare/about/
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
haematolog-ical 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)
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 Ceredase (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, Cerezyme 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 dispro-portionate 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 Cerezyme 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-butyldeoxy-nojirimycin (NB-DNJ: Zavesca; 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 Zavesca (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 Cerezyme, Zavescais given orally and does cross the blood–brain barrier (Platt et al, 1997), and clinical trials are currently also underway using Zavescafor type 3 GD However, Zavescacauses 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
Trang 6affect 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, Zavescahas 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, Zavescais 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
manage-ment and treatmanage-ment 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 endoplas-mic reticulum and degraded there, and chaperones, in
Table II Indications for choice of currently available GD treatments.
Enzyme replacement
therapy using Cerezyme
Substrate reduction therapy using Zavesca
First-line treatment for
Gaucher disease
Second treatment option when ERT is unavailable
or unsuitable
Paediatric disease Non-paediatric disease
Need for prompt response Slower response option
Patients planning to have
children or unable/unwilling
to use contraceptives
Patient must use contraceptives Lack of improvement/side
effects with SRT treatment
Supplemental to ERT
in severe cases
Trang 7principle, 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-deoxynojir-imycin, 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
thera-peutic 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
admin-istration 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
accumula-tion 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
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 Biochem-istry at the Weizmann Institute of Science
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