gaucher

Abstract
Objective: To review the epidemiology, pathophysiology, and treatments of Gaucher disease
(GD), focusing on the role of enzyme replacement therapy (ERT), andsubstrate reduction
therapy (SRT). Data Sources: A literature search through PubMed (1984-May 2013) of
English language articles was performed with terms: Gaucher’s disease, lysosomal storage
disease. Secondary and tertiary references were obtained by reviewing related articles. Study
Selection and Data
Extraction: All articles in English identified from the data sources, clinical studies using ERT,
SRT and articles containing other interesting aspects were included. Data Synthesis: GD is the
most common inherited LSD, characterized by a deficiency in the activity of the enzyme acid
β-glucosidase, which leads to accumulation of glucocerebroside within lysosomes of
macrophages, leading to hepatosplenomegaly, bone marrow suppression, and bone lesions. GD
is classified into 3 types: type 1 GD (GD1) is chronic and non-neuronopathic, accounting for
95% of GDs, and types 2 and 3 (GD2,
GD3) cause nerve cell destruction. Regular monitoring of enzyme chitotriosidase and
pulmonary and activation-regulated chemokines are useful to confirm the diagnosis and
effectiveness of GD treatment. Conclusions: There are 4 treatments available for GD1: 3 ERTs
and 1 SRT. Miglustat, an SRT, is approved for mild to moderate GD1. ERTs are available for
moderate to severe GD1 and can improve quality of life within the first year of treatment. The
newest ERT, taliglucerase alfa, is plant-cell derived that can be produced on a large scale at
lower cost. Eliglustat tartrate, another SRT, is under phase 3 clinical trials. No drugs have been
approved for GD2 or GD3.
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.
Epidemiology and Pathophysiology
GD is a systemic metabolic disorder caused by the accumulation of the lipid substrate GLC
within the monocytemacrophages system, resulting in the formation of Gaucher’s cells.3-8
These cells are the hallmark of the disease and are found in many organs mostly in bone, bone
marrow, liver, spleen, and lymph node parenchyma. Accumulation of Gaucher cells can also
enhance production of inflammatory cytokines, which cause enlargement of the spleen and
liver, destruction of bone, abnormalities in the lung, anemia, thrombocytopenia, and
leukopenia.3-8 Gaucher’s cells are about 20 to 100 μm in diameter, have small eccentric nuclei,
and cytoplasm with crinkles and striation.7
GD affects men and women equally. According to a report by the National Organization for
Rare Disorders, the GD incidence rate may be as high as 1 in 450 births among individuals
with Ashkenazi Jewish ancestry and 1:20 000 to 1:200 000 in the general population.9-13 The
National Gaucher Foundation estimated the incidence of GD1 in the United States to be about
1 in 20 000 live births or a prevalence of 1 in 40 000.14 A high prevalence of GD1, especially
with N370S and 84GG mutations, is seen among Ashkenazi Jews, whereas mutations in N370S
are found among North American, European, and Israeli populations.15,16 Mutations in the
GBA1 gene located at chromosome 1q21 were identified in GD patients. The 4 most common
mutations seen in 90% of disease alleles are identified as N370S, 84GG, L444P, and
IVS2+1.6,8,10 Mutations at position L444P correlated with a higher incidence of neurological
complications. 8,17 These mutation and nucleotide changes are classified according to current
nomenclature guidelines.8,17 GD is classified into GD1 (non-neuronopathic), GD2
(acute neuronopathic), and GD3 (chronic neuronopathic) according to the presence of
neurological deterioration, age at identification, and disease progression rate.15,18 The
features of each subtype of GD are summarized in Table 1.15
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
Possible pathophysiology of GD includes defects in enzyme, gene, and/or packing of the
lysosomes.7,34-38
Defects in the function of lysosomes result in mis-sorting or loss of function of lysosomal
proteins.35 Normal lysosomal proteins are usually tagged with a carbohydrate that allows their
recognition and transport via the mannose-6-phosphate receptor.34,36 However, mutation in
this has been identified in GD patients.34,36,37 Additionally, one of the lysosomal hydrolases,
GBA1, which is important for degradation of GLC into glucose and ceramide, was found to be
defective/deficient, and this enzyme is improperly packed in GD patients, leading to
accumulation of GLC in the monocyte-macrophage system.7,36,39
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.
Therapeutic Options Enzyme Replacement
Therapies ERTs work by supplementing the defective GBA1 with
active enzyme, which catalyzes the hydrolysis of GLC into glucose and ceramide, thus
reducing the accumulated GLC in the liver, spleen, bone marrow, and other organs.61,62 The
introduction of the first ERT in 1991, the placental-derived macrophage-targeted
glucocerebrosidase, alglucerase (Ceredase, Genzyme Corp) led to a revolution in GD
management, and this finding also introduced the option of using ERT for other LSDs.15,63
Imiglucerase (Cerezyme, Genzyme Corp), an analog of glucocerebrosidase produced by DNA
technology using Chinese hamster ovary cells, was approved by the Food and Drug
Administration (FDA) in 1994 and subsequently replaced alglucerase. However, in June 2009,
Genzyme Corp. announced a viral contamination at its manufacturing site.64,65 The dramatic
reduction in global supply to 20% left the ERT unavailable to many patients worldwide. This
shortage stimulated interest in the development of 2 new ERTs.15
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 βglucocerebrosidase, 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.
Clinical Trials on Taliglucerase Alfa
A phase-1, single-center, non-randomized, open-label clinical trial studied the safety and
pharmacokinetics of taliglucerase alfa in 6 healthy volunteers for 4 weeks. The volunteers
received 15 units of taliglucerase/kg intravenously (IV) on day 8, 30 units/kg IV on day 15,
and 60 units/kg IV on day 22. The results of the study showed median serum half-lives of 15
minutes for doses of 30 or 60 units/kg IVs, and volume of distribution was 34 to 94 mL/ kg.2,70
Neither adverse reactions nor development of antibodies was detected in these volunteers. After
phase 1, the FDA waived the requirement for conducting a phase 2 trial and allowed the
company to conduct phase 3 clinical trials. A phase-3 randomized, double-blind, multicenter,
parallelgroup clinical trial with 31 GD1 patients aged 19 to 74 years with enlarged spleens
(greater than 8 times normal) and thrombocytopenia (less than 120 000/mm3) was conducted
to observe the safety and efficacy of taliglucerase alfa. To this end, 15 patients were given 30
unit/kg IV, whereas 16 patients were given 60 unit/kg IV once every 2 weeks for 9 months.7173 It was found that 10 patients had anemia at baseline, but patients with severe neurological
symptoms, as manifested in GD2 or GD3, were excluded because taliglucerase alfa is intended
to treat GD1 only. The primary
end point observed was the decrease in spleen volume. The secondary end points observed
were a decrease in liver volume, an increase in hemoglobin and platelet levels, and a decrease
in plasma CT activity.62,72 The group that conducted the study reported the data without
statistical calculations but based on changes before and after treatment.
Reductions in spleen volumes of 29% and 39% were observed in patients given 30 unit/kg IV
and 60 unit/kg IV,
respectively. Furthermore, a 13% and 19% reduction in liver volume and a 15% and 64%
increase in platelet count
were observed in the groups that were treated with 30 unit/ kg IV and 60 unit/kg IV,
respectively. CT activity decreased rapidly in a dose-dependent manner. Patients with anemia
at baseline had significant improvements in their hemoglobin levels. No serious adverse
reactions were reported. One patient who developed a hypersensitive reaction and one who
developed a mast-cell-mediated reaction were able to continue the treatment with
premedication with antihistamines. 73 The remaining adverse reactions included mild to
moderate abdominal pain, headache, and pruritis.
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.
A phase 3 randomized, multicenter, open-label, singlearm, clinical trial enrolled 25 patients
aged 13 to 66 years to compare the effect of switching from imiglucerase to taliglucerase
alfa.62 These patients had received imiglucerase ranging from 11 to 60 units/kg IV for a
minimum of 2 years and had been stable on biweekly doses prior to switching to taliglucerase
alfa. Imiglucerase therapy was stopped prior to the treatment with taliglucerase alfa.
Taliglucerase alfa was given every other week, at doses similar to the patient’s previous
imiglucerase dose. To maintain the effective clinical parameter as imiglucerase, 1 patient was
given an increased dose of 10 units/kg taliglucerase alfa. The primary and secondary end points
measured were the following: spleen volume, liver volume, hemoglobin, and platelet counts.
After 9 months of treatment with taliglucerase alfa, stable primary and secondary end points
were achieved.62 This study showed that patients could be switched from imiglucerase to
taliglucerase alfa and vice versa safely with only some minor adjustments. An ongoing,
multicenter, double-blind phase 3 trial is being conducted with GD pediatric patients aged 2 to
18 years for 12 months. Patients received 30 units/kg or 60 units/kg every 2 weeks. For further
information and other ongoing trials on taliglucerase alfa, please refer to
http://clinicaltrials.gov/ct2/results?term=taliglucerase.75
Common hypersensitivity reactions and production of antibodies may occur, but it is unclear
if the allergic reaction
differs from that in the other 2 ERTs, that is, imiglucerase or velaglucerase alfa. All 3 ERTs
are incapable of crossing the blood-brain barrier and are specifically indicated for moderate to
severe GD1 treatment.2 According to International Collaborative Gaucher Group (ICGG),
there are more than 4000 patients receiving imiglucerase and more than 1000 patients
worldwide who are treated with velaglucerase alfa.
Substrate Reduction Therapy
In contrast to ERT, which aims to replace the defective enzyme with active enzyme, SRT
targets the biosynthetic
cycle and reduces the load of GLC influx into the lysosome. Miglustat (Zavesca, Actelion
Pharmaceutical Limited,
Switzerland) is a synthetic D-glucose analog, which works by inhibiting the enzyme GLCsynthase, the enzyme responsible for GLC synthesis and other glycosphingolipids, thus
reducing the GLC to residual activity and preventing its influx into the lysosome.78,79 The
drug was approved in 2002 by the European Medicines Agency and by the FDA in 2003 for
mild to moderate treatment of GD3. The recommended dose for this oral drug is 100 mg, 3
times daily. The drug can penetrate the blood-brain barrier and was intended as a prototype the
management of neuronopathic forms of GD (GD2 and GD3). Although SRT offers more
convenient dosing than ERTs (oral versus IV), clinical trials with miglustat in GD3 patients
showed no improvement in neurological
conditions.13,80 The drug also caused a higher incidence of adverse reactions such as tremor
(30%), diarrhea (85%), weight loss (65%), reduced platelet counts, numbness, and feeling of
burning on hands and feet.79,81 Moreover, longterm reduction of glycosphingolipids could
affect a variety of cell functions because of the essential roles of these lipids.
82 Miglustat is now only approved in Europe, Israel, and the United States for patients who
cannot take ERT because of anaphylactic reactions.7 The pregnancy category of miglustat is
X, whereas that of velaglucerase alfa and taliglucerase alfa is category B and imiglucerase is
C.61,62,79,80,83 Another SRT, eliglustat tartrate (Genz-112638, Genzyme Corp) has recently
begun phase 3 clinical trials. Eliglustat is
a ceramide analog that works by inhibiting GLC synthase, thereby reducing endogenous
production of GLC.84 A phase 2, multinational, open-label, single-arm clinical trial was
conducted in 28 GD1 patients aged 18 to 65 years to evaluate efficacy, safety, and
pharmacokinetics of eliglustat administered twice daily orally at 50 or 100 mg for 52
weeks.3,84 Inclusion criteria of the study were deficiency in GBA1, a spleen volume 10 times
that of the normal value, thrombocytopenia, and/or anemia. Statistically significant
improvements in hemoglobin level (1.62 g/dL; 95% CI = 1.05-2.18 g/dL), platelet count
(40.3%; 95% CI = 23.7-57 g/dL), spleen volume (−38.5%; 95% CI = −43.5% to -33.5%), liver
volume (−17%; 95% CI = −21.6% to -12.3%), and lumbar spine bone mineral density (Z score
= 0.31; 95% CI = 0.09-0.53) were observed. Decrease in biomarkers (CT, angiotensinconverting enzyme, PARC/CCL18, tartrateresistant acid phosphatase) by 35% to 50% was also
achieved.84 A phase 2, multisite, open-label, single-arm clinical study with the same patients
(total 20) and same group of researchers was conducted for 2 more years. Statistically
significant (P < .001) improvements were seen in primary and secondary end points.
Statistically significant increases in platelet count and hemoglobin level and decreases in spleen
and liver volumes were observed.85 Additionally, significant increase in lumbar spine bone
marrow density (BMD) and T score and decrease in bone marrow infiltration by Gaucher cells
were also recorded.85 Several phase 3, randomized, multicenter, multinational, cross-over
clinical trials are being conducted on eliglustat to confirm its efficacy, safety, pharmacokinetic
properties, and relative bioavailability; to compare the efficacy in patients switching from ERT
to eliglustat; and to evaluate once daily versus twice daily dosing efficacy. These are listed on
http://www.clinicaltrials.gov/ct2/results?term= eliglustat tartrate .86 Eliglustat will likely get
FDA approval soon. This drug is predominantly metabolized by CYP2D6; therefore, patients
who are slower in metabolizing this enzyme should be dosed accordingly.87 Because eliglustat
does not penetrate the blood-brain barrier, it may not add value in the treatment of GD1
patients.
Supportive Care for GD
In addition to ERT or SRT, other management options are used either alone, or together with
ERT or SRT, to alleviate specific disease symptoms such as bone disease, hepatosplenomegaly,
bleeding, pulmonary hypertension, seizures, and Parkinsonism. Bone disease usually indicates
advanced stages of GD, but patients’ susceptibility to fractures, osteopenia, and osteonecrosis
can also be a sign of GD in asymptomatic patients.35 Treatment of bone disease with oral
bisphosphonates such as alendronate disodium 40 mg/d, calcium 1500 mg/d, and vitamin D
400 IU/d for 24 months significantly improved BMD and bone mineral content and decreased
fracture risk as compared with placebo and calcium 1500 mg/d and vitamin D 400 IU/d.88,89
However, alendronate did not improve focal bone lesions (deformity in distal femur and
vertebral and pelvic bones), showing a more complex osteoclast-mediated mechanism of GD
that need further studies. Alendronate at a high dose of 40 mg/d may provide benefit and could
be an effective and safe way to increase BMD and bone mineral content.88,89 In severe
thrombocytopenia or symptomatic organomegaly unresponsive to ERT, splenectomy might be
performed.35 Defects in platelets, coagulation, and non-corrected thrombocytopenia pathways
may cause increased bleeding risk in GD patients and require constant monitoring.35
In patients with moderate to severe GD with life-threatening complications such as
hepatopulmonary syndrome and pulmonary hypertension, higher doses of and longer treatment
with imiglucerase, such as 120 units/kg, may be needed along with adjuvant therapy such as
vasodilators and/or warfarin.90 For visceral and neurological complications, the best current
option is to use higher doses of ERT.91 Although the majority of GD patients never develop
clinical signs of Parkinsonism, those who manifest the symptoms may experience
improvements in or worsening of their symptoms despite optimal ERT. Some studies showed
that posteroventrolateral pallidotomy can either improve or worsen Parkinsonism
symptoms.92-95 Because of the severity and complexity of GD, providers need to
individualize treatment options for complicated GD because no guidelines are available
currently.
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.