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Objective: To Review The Epidemiology, Pathophysiology, and Treatments of Gaucher Disease
Objective: To Review The Epidemiology, Pathophysiology, and Treatments of Gaucher Disease
Gaucher disease (GD) the most common autosomal recessive lysosomal storage disease (LSD)
was first described by Philippe Gaucher in 1882.1 This was the first identifie LSD caused by
deficiency or absence of the activity of the enzyme acid β- glucosidase, also known as
glucocerebrosidase or glucosylceramidase E.C.3.2.1.45 (GBA1), leading to accumulation of
glucocerebroside also known as glucosylceramide (GLC) in tissue macrophages.2 The
development of 2 effective enzyme replacement therapies (ERTs; imiglucerase [Cerezyme]
and velaglucerase alfa [VPRIV]) for GD and recently, the discovery of a new plant-derived
ERT (taliglucerase alfa [ELELYSO]) has made treatment of GD1 possible. This review
summarizes the disease epidemiology, pathophysiology, diagnosis and useful biomarkers, and
available treatment options with a focus on the newest ERT taliglucerase alfa and the newest
substrate reduction therapy (SRT) eliglustat tartrate. Several unresolved issues and future
options for GD therapies are also discussed briefly.
GD1 occurs mainly in adults and is the most frequent, accounting for 95% of GD cases.10 If
GD onset occurs prior to adulthood, a more rapidly progressing disease is suspected. GD1 is
associated with visceral complications without CNS involvement. Initial manifestations
normally begin with splenomegaly, hepatomegaly, anemia, leukopenia, and
thrombocytopenia.19 Further progression involves gastrointestinal complications such as
portal hypertension, cirrhosis, ascites, esophageal hemorrhage, and bone lesions manifested as
chronic bone pain, skeletal deformities, osteonecrosis, osteopenia, and osteoarticular
infections.19-24 Increased risk of cholelithiasis is present in women older than 40 years.19
Interstitial lung disease, pulmonary hypertension, polyclonal gammopathy, and peripheral
neuropathy have also been observed in GD1 patients.17,19,23-26
GD2 and GD3 are neuronopathic variants with several distinguishing characteristics. GD2 is a
rare disease occurring in fewer than 1 in 100 000 people and generally affects infants 4 to 5
months old. It involves the brain, spleen, liver, and lungs, with severe neurological
complications. The disease progresses rapidly, leading to death within the first 2 years of
life.5,10,22,27-29 GD3 is also a rare form that affects fewer than 1 in 100 000 people and is
further divided into subgroups: 3a, 3b, and 3c.10,15,29 GD3a has only mild visceral
manifestations but causes severe, progressive myoclonic seizures, which can lead to death
within the first 2 decades.30 GD3b involves more visceral features, such as massive
hepatosplenomegaly, growth retardation, and supranuclear gaze palsy. GD3c patients with the
D409H allele, a rare cardiac mitral and aortic calcification, will often die in early
adulthood.15,31,32 GD1 can also be classified according to clinical severity scores using a new
scoring system, Gaucher Disease Severity Score Index, Type I (GauSSI-I). 33 This scoring
index was developed to provide a more thorough and reliable method to correlate the
differences in genotypes and phenotypes of the patients, to correlate to patients’ response to
biological markers, and to account for the variability in clinical response and severity of the
disease. This score index provides a more thorough system than the only one previously
available—the Zimran Severity Score Index. According to GauSSI-I, there are 6 domains to
score from: skeletal, hematological, biomarker, visceral, lung, and neurological. Table 2 shows
the GauSSI-I scoring system withexplanations. There are 42 points, with higher points
reflecting more severe GD.33
There are possible links between mutations in the GBA1 gene and risk of Parkinsonian
syndrome in GD patients.
Several clinical studies showed that patients with Parkinson’s disease and associated Lewy
body disorders had an increased frequency of GBA1 mutations as compared with control
individuals.40-42 Parkinsonian syndrome characteristics such as olfactory dysfunction,
myoclonus seizures, bradykinesia, resting tremor, and rigidity in GD1 are believed to arise
from synuclein aggregation within dopaminergic neurons induced by either a mutation in
GBA1 (common mutated alleles are N370S, L444P), leading to protein misfolding, or
accumulation of glycosphingolipids, predominantly GLC. This misfolding protein may kill
dopamine-producing nerve cells, causing abnormal movement and balance problems as seen
in GD with Parkinsonian syndrome.43,44 Diagnosis and Biomarkers GD is normally
diagnosed during initial clinical examination by the presence of unexpected anemia,
thrombocytopenia, and organomegaly.15 Clinical diagnoses are confirmed by biochemical
diagnosis.7 Detection of low enzymatic activity of GBA1 in peripheral blood compared with
normal control is still the gold standard for diagnosing GD. Despite this test being available
for nearly 4 decades, many patients are still incorrectly diagnosed.15,21,45 The assay is
performed in 10 cc of blood leukocytes using a fluorescent substrate, 4-methyumbelliferone β
glucosidase. The sample can be shipped at ambient temperature overnight to diagnostic
laboratories.16,21,46,47
Biomarkers can add quality assurance to biochemical diagnosis. Ongoing studies are conducted
to detect useful protein biomarkers for GD through survey of protein composition of bodily
fluids, cells, or tissue specimens of symptomatic patients with GD. Non-specific biomarkers
such as tartrate-resistant acid phosphatase, angiotensin-converting enzyme, hexosaminidase,
and cathepsins K have been used for routine monitoring; however, their levels are also observed
in healthy individuals.48-50 Increases in interleukin (IL)-1β, IL-6, IL-10, TNF-α, macrophage
inflammatory proteins (MIP)-1α, MIP-1β, and soluble CD 163 have also been used as
biomarkers for GD; however, corrections in plasma MIP-1α and MIP-1β after treatments are
not proportional to those found with true Gaucher cell biomarkers.7,51-53 Activated
macrophages also cause secretion of the enzyme chitotriosidase (CT), which plays a role during
the remodeling phase of the tissue healing process and immune chemotaxis.54,55 CT, a
macrophage-derived chitin-fragmenting hydrolase, is massively expressed in lipid storage
tissue macrophages. Common tissue macrophages do not produce CT.8,34 Patients with LSD,
sarcoidosis, thalassemia, visceral Leishmaniasis, leprosy, and other diseases usually have an
elevated CT level.34,54,55 Recently, plasma CT has been used as a first screening in
diagnosing GD. In patients with high clinical severity scores, CT levels were usually greater
than 20 000 nmol/mL/h.33,56 After treatment, CT values are expected to decrease. However,
even after treatment, more severely affected patients will have less reduction in plasma CT
activity. A smaller-than-expected reduction in plasma CT activity after the initial treatment can
also be used as a clinical parameter to increase the dose of the drugs such as ERTs or SRTs.56
Massive overproduction and secretion of pulmonary and activation-regulated chemokines
(PARC/CCL18), which are 10- to 40-fold elevated in symptomatic patients with GD can also
be used as a biomarker.57,58 Because PARC/CCL18 is a small molecule, its level in urine is
proportional to the level in circulation.59 Measurement of plasma PARC/
CCL18 has been a useful additional tool to monitor changes in Gaucher cells and a useful tool
to evaluate GD patients who are CT deficient.60 Therefore, regular monitoring of CT or
PARC/CCL18 in CT-deficient patients, along with radiological monitoring of the bone marrow
and skeleton, and other sensitive assays are needed to confirm the diagnosis of GD and to
monitor the effectiveness of treatment.
In 2010, velaglucerase alfa (VPRIV, Shire Human Genetics Therapies Inc), an analog of
recombinant glucocerebrosidase produced in human fibroblast cell lines, became the third ERT
approved by the FDA.61 In May 2012, FDA approved taliglucerase alfa (ELELYSO, Pfizer
Inc, or, outside the United States, Protalix BioTherapeutics), which is made genetically by
modified carrot cells.2,36,62 Comparison between taliglucerase alfa, imiglucerase, and
velaglucerase alfa showed that taliglucerase alfa has 2 additional amino acids at the N-terminus
derived from the linker used for the fusion of the signal peptide, and it has an additional 7
amino acids at the C-terminus derived from the vacuolar targeting signal.66 Although the
amino acid compositions of imiglucerase and taliglucerase alfa differ from the human β-
glucocerebrosidase, whereas velaglucerase has the
same amino acid sequence as humans, X-ray structures of all 3 ERTs were similar.67
Taliglucerase alfa differs from velaglucerase alfa and imiglucerase in its glycosylation because
it contains core α-(1,2)-xylose and α-(1,3)-fucose that are unique to plant-derived proteins.
Velaglucerase alfa contains longer-chain high mannose-type glycans, and imiglucerase has a
normal core mannose structure.66,67 A study showed that the differences in glycosylation of
a drug affect its internalization into human macrophages. However, another study that used
various expressions of mannose receptor binding or used mannose residue failed to show any
differences in macrophage uptake.3,68,69 Table 3 summarizes important information such as
dosing, pharmacokinetics, pregnancy category, and adverse drug reactions and describes how
to administer from all 3 available ERTs and 1 SRT, which is useful for the practicing clinician.
A phase 3 randomized, double-blind, multicenter, parallelgroup clinical trial, which was the
extension of the above
phase 3 trial, was conducted with the same group of patients (only enrolled 26 patients) and
same doses of taliglucerase alfa, given at 30 unit/kg IV and 60 unit/kg IV every 2 weeks for an
additional 15 months (patients received a total of 24 months of treatment).67 Patients
demonstrated improvements
in primary and secondary end points. Patients treated with 60 units/kg of taliglucerase alfa
showed a 51% reduction in spleen volume, whereas patients treated with 30 units/kg showed a
41% reduction. Platelet count increased significantly by 69% in the 30 units/kg group, with
slight improvement in the 60 units/kg group. CT activity was reduced by 76% in the 60 units/kg
group and by 61% in the 30 units/kg group. One patient who experienced an intravenous
hypersensitivity reaction was able to continue treatment with premedications.74,75 To detect
if Gaucher cells could infiltrate bone marrow, 8 patients’ bone marrow samples were measured
by Dixon Quantitative Chemical Shift Imaging.71 This magnetic resonance imaging technique
measures displacement of fatty marrow by Gaucher cells and is a sensitive and useful tool to
measure response of bone marrow to ERT.76 After 12 to 24 months of treatment with
taliglucerase alfa, patients showed early and sustained increases in levels of bone marrow fat
fractions as compared with untreated patients.
Future GD Therapies
In recent years, there have been a few studies showing promising results using gene therapy
and chaperone treatment in animals. Gene therapy administers and incorporates a healthy
gene using viruses as vectors/carriers to replace defective genes. Studies using murine GD1
models injected with lentiviral- and null mice GD models injected with adeno-associated
viral (AAV8)-serotype vector harboring the human GBA1 gene have shown very promising
result. These vectors induce the liver to secrete GBA1
in young animals and older mice models with GD.
Chaperone therapy is based on the ability of small molecules to interact with mutant proteins
that are misfolded
because abnormal protein folding has been recognized as a common mechanism in many
inherited diseases.19
Chaperone molecules are usually weak inhibitors that bind to GBA1 at a neutral pH during
biosynthesis of the enzyme; they stabilize the enzyme for delivery to the lysosome, then
dissociate from the enzyme, thus allowing GBA1 to be delivered to the normal site.99,100
However, phase 1 and 2 clinical trials using isofagomine as a chaperone (developed by Amicus
Company) in fibroblasts cultured from GD patients showed disappointing results.99 Although
chaperone therapy may not be used as monotherapy, in the future, it might be an option for
combination treatment strategies.
Unresolved Issues
Unresolved issues in GD that still need to be addressed include the following: whether
asymptomatic patients need treatment, what are the effective doses of ERTs or SRTs, should
patients commit to a lifetime therapy with ERT or SRT, do providers globally have the
experience needed to diagnose and to treat GD, is there any possible association between GD
and other diseases, and when will treatment options become available for GD3. Although many
providers think that all patients should be treated, some are convinced that a “wait and see
approach” has merit in very mildly affected patients.15 Attempts to compare the efficacy of
low-dose regimens with higher-dose and more costly regimens have been made in several case
series. Unfortunately, diversity of the patients, age, disease severity, and the small number of
patients being evaluated make comparing regimens
in those cases difficult.101 Because the incidence of GD is rare in some countries, the providers
who have not
seen GD cases may not have the experience to diagnose and treat GD. Finally, we still need to
learn if there is any association between GD, cancers, cardiovascular disease, and life
expectancy and how to treat this.