Information about Glucocerebrosidase
The current standard treatment for type 1 Gaucher disease is enzyme replacement therapy using infusions of natural or recombinant forms of glucocerebrosidase, the lysosomal enzyme that is deficient in Gaucher disease.
Liver safety of Glucocerebrosidase
Enzyme replacement therapy is generally well tolerated and has not been linked to serum enzyme elevations or to instances of clinically apparent acute liver injury.
Mechanism of action of Glucocerebrosidase
Glucocerebrosidase is a lysosomal enzyme that is deficient or defective in the inherited condition known as Gaucher disease. The enzyme acts in lysosomes upon the sphingolipid glucocerebroside, catalyzing its conversion to glucose and ceramide.
History of Glucocerebrosidase
Glucocerebrosidase is an important step in the metabolism of glycolipids and its absence leads to accumulation of glycosylceramide in macrophages, giving rise to "foam cells" particularly in the spleen, liver and bone, leading to splenomegaly, hepatomegaly and bone dysplasia.
In type 1 Gaucher disease, the most common form of this disease, the tissue damage is mostly limited to liver, spleen and bone, but sometimes involves lung and kidney.
In types 2 and 3 Gaucher disease, there is also neurologic accumulation of foam cells and damage, leading to severe neurologic outcomes in infancy or childhood. Infusions of glucocerebrosidase have been shown to increase the activity of this enzyme intracellularly, to decrease foam cells and to ameliorate the signs of symptoms of type 1 Gaucher disease.
The initial forms of glucocerebrosidase (alglucerase) used to treat patients were prepared from human tissue, largely placentas. Subsequently, recombinant forms of glucocerebrosidase were developed (imiglucerase, velaglucerase, taliglucerase) that have improved and more prolonged activity, allowing for less frequent infusions with better tolerance. All forms of glucocerebrosidase used clinically have been generally well tolerated with only mild adverse events, largely due to local or hypersensitivity reactions. None of the natural or recombinant forms of the enzyme have been linked to liver injury.
Alglucerase (al gloo' ser ase) is a placenta-derived form of purified glucocerebrosidase that was approved for use in type 1 Gaucher disease in the United States in 1991, the first drug approved as an enzyme replacement therapy. Alglucerase was typically administered three times weekly, and was withdrawn from use when recombinant forms of glucocerebrosidase became available that could be administered every 1 to 4 weeks, and appeared to have equal if not superior efficacy and similar or fewer side effects. Alglucerase is no longer commercially available.
Imiglucerase (im" i gloo' ser ase) was the first recombinant form of glucocerebrosidase approved for therapy of type 1 Gaucher disease. Imiglucerase is prepared by recombinant techniques using Chinese hamster ovary cells. It differs from the native enzyme in one amino acid (histidine at position 495 instead of arginine) and by modification of the glycosylation sites so that they terminate in mannose sugars, which are specifically recognized and taken up by macrophages. Imiglucerase was approved for use in the United States in 1994 and soon became the most widely used enzyme replacement therapy for Gaucher disease. It is available as a lyophilized powder in vials of 200 and 400 Units. The typical dose is 60 Units/kg given by intravenous infusion over 1 to 2 hours every two weeks. Side effects are uncommon and generally mild, but can include local infusion site reactions, fatigue, headache, dizziness, abdominal pain, nausea, diarrhea, back pain, fever and rash. Rare, but potentially severe adverse reactions include hypersensitivity reactions and anaphylaxis.
Velaglucerase (vel" a gloo' ser ase) alfa was the second recombinant form of glucocerebrosidase approved as therapy of Gaucher disease. Velaglucerase is produced in a human cell line using gene activation technology, resulting in production of a recombinant protein with the identical amino acid sequence as the native, human enzyme. The glucocerebrosidase producing cells are treated with enzymes that modify glycosylation and result in high-mannose type glycans which increase uptake of the velaglucerase by macrophages. Velaglucerase was approved for use as enzyme replacement therapy of type 1 Gaucher disease in the United States in 2010. It is available as a lyophilized powder in single use vials of 400 Units under the brand name Vpriv. The typical initial dose is 60 Units/kg intravenously every 2 weeks. Side effects are not common and usually mild, but can include local infusion reactions, fatigue, headache, dizziness, abdominal pain, nausea, back pain, joint pain and fever. Rare, but reported severe adverse reactions include hypersensitivity reactions and anaphylaxis.
Taliglucerase (tal" i gloo' ser ase) alfa was the third recombinant form of glucocerebrosidase approved for therapy of type 1 Gaucher disease. Taliglucerase is prepared in plant cell cultures transfected with the human glucocerebrosidase gene. Taliglucerase differs from the native enzyme by two amino acids at the N terminal and 7 amino acids at the C terminal end. It is glycosylated and the oligosaccharide chains have terminal mannose sugars, which increase its uptake by macrophages. Taliglucerase was approved for use as enzyme replacement therapy for type 1 Gaucher disease in the United States in 2011. It is available as lyophilized powder in single use vials of 200 Units. The typical dose is 60 Units/kg every two weeks administered intravenously over 1 to 2 hours. Side effects are not common and usually mild, but can include local infusion reactions, fatigue, headache, dizziness, abdominal pain, nausea, back pain, joint pain and fever. Rare, but reported severe adverse reactions include hypersensitivity reactions and anaphylaxis.