What type of enzyme is glucocerebrosidase?

Treatment
The main goal is to improve the patients’ quality of life by allowing them to perform their normal daily activities, such as working without feeling the excess fatigue or walking normally without experiencing joint pain. Other goals include preventing the severity of complications, such as reduced bone density to thinning, weak bones (osteoporosis) and easy fractures or shortness of breath from the reduced lung function. Normalizing the growth for a child for them to reach a normal height can also be a target within a couple of years of treatment and achieving a normal onset of puberty.

Treatment is individualized for each patient depending on the type of Gaucher disease. Type 1 Gaucher disease is considered treatable and mild, because it does not involve neurological symptoms since the brain is not affected. Type 2 is not considered to be treatable at this point due to the quick and irreversible brain damage in the infantile years. Type 3 still involves neurological damage, but these symptoms progress more slowly than in type 2. There are current FDA-approved drug therapy options that include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT).

Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type 1. In studies of ERT, anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types 2 and 3 who receive ERT. However, ERT has not been effective in reducing or reversing certain neurological symptoms associated with Gaucher disease types 2 and 3.

ERT is given every 2 weeks via intravenous (IV) infusions either at infusion centers, National Gaucher Disease Treatment Center, or at home by self-administration, assistance from a family member/friend or home care nurse. The three current FDA-approved ERT drugs include imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase (Elelyso).

The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the U.S. Food and Drug Administration (FDA) in 1991 for the treatment of Gaucher disease type 1. It was the first ERT proven effective for the treatment of Gaucher disease type 1.

The synthetic form of this drug, imiglucerase (Cerezyme), was approved in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human placentas. Therefore, Ceredase has been withdrawn from the market due to similar drugs being made without having bioavailability issues from human derived cells and the transfer of diseases. Cerezyme, manufactured by Genzyme, replaces the human lysosomal enzyme glucocerebrosidase that is lacking in individuals with Gaucher disease.

Another FDA approved preparation of glucocerebrosidase called Velaglucerase alfa (trade name VPRIV) produced in a continuous human cell line is available from Shire.

Elelyso (also known as Uplyso or taliglucerase alfa) by Pfizer Inc., under license from Protalix BioTherapeutics Inc., was approved by the FDA in 2012 as a treatment for Gaucher disease type 1. Elelyso is an injected long-term enzyme replacement therapy that should be administered by a health care professional every other week. It uses genetically engineered carrot cells to provide replacement glucocerebrosidase.

Substrate reduction therapy may also be utilized in specific patient populations. These work differently than the ERT’s by blocking the production of glucocerebroside (fatty substance) by inhibiting the enzyme glucosylceramide synthase. These come in tablets/capsules and are taken daily. SRT’s are not to be used in children and teenagers, pregnant or breastfeeding women, elderly patients, and people with severe kidney or liver disease. The two current FDA-approved drugs include eliglustat (Cerdelga) and imiglustat (Zavesca).

In 2014, Cerdelga (eliglustat), manufactured by Genzyme, was approved by the FDA for the long-term treatment of adult patients with the Gaucher disease type 1.

In 2003, the U.S. Food and Drug Administration approved Zavesca, an oral therapy, for the treatment of adult patients with mild to moderate Gaucher disease type 1 for whom enzyme replacement therapy is not a treatment option (as a result of allergy, hypersensitivity, etc.).

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

There is current research at the Medical Genetics Branch of the National Human Genome Research Institute about a possible link or association between Gaucher disease and Parkinson disease. Studies have shown that affected individuals (with two disease-causing GBA gene mutations) and carriers (with a single GBA gene mutation) both have an increased risk of Parkinson disease.

Individuals with Gaucher disease are at increased risk for multiple myeloma, and as adults should be monitored carefully.

Previously, a diagnosis of Gaucher disease was often made by the presence of Gaucher cells in a bone marrow aspirate or when a patient presented with an unexplained massive splenomegaly and was treated with splenectomy. However, these diagnostic methods were not accurate because many storage cells, so-called pseudo-Gaucher cells, may be confused with Gaucher cells on the marrow examination. Nevertheless, a bone marrow examination may still be needed in patients where the splenomegaly does not regress on treatment, or if the patient develops enlarged lymph nodes or B symptoms that suggest development of a lymphoma.1

What is the glucocerebrosidase enzyme activity test?

Measurement of glucocerebrosidase enzyme activity in leukocytes or skin fibroblasts on a skin biopsy is considered the ‘gold standard’ for diagnosing Gaucher disease.1,3 Dried blood spots are used as a screening assay for glucocerebrosidase enzyme activity.4 A test using approximately 5 mL of EDTA or heparinised blood is all that is necessary to confirm a diagnosis of Gaucher disease as this allows direct measurement of glucocerebrosidase activity in leukocytes.5,6 If patients have leukopaenia, cultivated skin fibroblasts from a skin biopsy can be assayed instead.5 The determination of Gaucher disease must be made by specialised laboratories with particular experience in the measurement of glucocerebrosidase activity and its interpretation.5-9 In patients with Gaucher disease, glucocerebrosidase activity levels are approximately 10‒30% of normal.8,9

Residual glucocerebrosidase enzyme activity has been shown to significantly correlate with age, chitotriosidase enzyme activity, spleen size and greater disease severity in patients with Gaucher disease.10 Yet, measuring glucocerebrosidase enzyme activity does not distinguish between patients with Gaucher disease who are heterozygote carriers of mutations in the GBA1 gene and individuals who do not have Gaucher disease. Moreover, this diagnostic blood test does not provide histological information on the bone, liver or spleen for diagnosis.1 However, a statistically significant relationship between the residual enzyme activity of glucocerebrosidase and bone involvement has been previously noted.10

Clinical experience in diagnosing Gaucher disease

Results were reported from the biochemical diagnosis of blood samples taken from 5128 patients with suspected Gaucher disease from the Biochemical Genetics laboratory in Egypt. For each patient, 5 mL of whole blood were collected by venous puncture into EDTA tubes. Plasma was obtained for chitotriosidase assay and leukocytes were separated to determine the activity of glucocerebrosidase using synthetic substrate. In all cases, measurement of glucocerebrosidase activity was conducted in parallel with the assessment of chitotriosidase in peripheral leukocytes. In healthy unaffected individuals without Gaucher disease, normal enzyme activity was reported as 1‒5 µmol/g prot/h for glucocerebrosidase and 4‒80 µmol/L/h for chitotriosidase.11

Of the 5128 suspected cases of Gaucher disease, 882 patients (17%) were diagnosed with the disease. Most of these patients (81.5% [719/882]) showed positive parental consanguinity; the male to female ratio was 1.6 to 1. The age range for diagnosis was from 3 months to 45 years, with 97.5% of patients diagnosed between the ages of 1.7 to 8 years. A decrease in the activity of glucocerebrosidase was evident in 99% of patients diagnosed with Gaucher disease. The mean glucocerebrosidase activity value in these patients represented 0.3 µmol/g prot/h, which was 30% of the low normal value. In these patients, chitotriosidase activity levels were increased (mean [standard deviation (SD)] 6243 [20,211] µmol/L/h). However, in nine patients, chitotriosidase levels were zero, and glucocerebrosidase activity was 45% of the low normal value.11

In 103 cases of suspected Gaucher disease, an elevation in mean (SD) chitotriosidase activity (131.8 [24.0] µmol/L/h) was noted; however, mean glucocerebrosidase (3.2 µmol/g prot/h) levels were normal.11

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Simplified diagram of the synthesis and trafficking of GCase in a functional cell. 1) GBA1, the gene coding for GCase, is transcribed into mRNA that is then transported out of the nucleus to the ER. 2) GCase is synthesized in the ER, where it binds to the protein LIMP2 in the favorable neutral pH of the cytoplasm. 3) LIMP2 transfers GCase through the Golgi. 4) GCase is then transferred to a late endosome. 5) When the late endosome fuses with a lysosome to form an autolysosome, LIMP2 disengages from GCase due to the decrease in pH. In the lysosome, GCase is activated by SAPC. GCase actively hydrolyzes its substrates GlcCer and GlcSph in this compartment