ChEMBL

On May 1, the FDA approved taliglucerase alfa for the treatment of Type I Gaucher's disease. Gaucher's disease is the most common of the lysosomal storage diseases. It is a hereditary disease caused by a deficiency of the enzyme β-glucocerebrosidase (Uniprot: P04062), also called β-Glucosidase. Gaucher's disease is a rare genetic disease with an incidence of 1 in 50,000 births and is considered an orphan disease. Type I Gaucher's disease is about 100 times more common in people of Ashkenazi jewish descent compared a north American population. Symptoms of type I Gaucher's disease begin typically in early adulthood and include enlarged liver and grossly enlarged spleen, impaired bone structure, anemia and low platelet levels, leading to prolonged bleeding and easy bruising. If enzyme replacement therapy (ERT) is available, the prognosis for patients with type I Gaucher's disease is good.

β-Glucocerebrosidase is an enzyme of 536 amino acids and molecular weight of approximately 59.7 kDa. The gene for β-glucocerebrosidase is located on the first chromosome (1q21) and catalyzes the hydrolyzation of glucocerebrosides (eg. ChEBI:18368), a process required for the turnover of the cellular membranes of red and white blood cells.  Macrophages clearing these cells fail to metabolize the lipids, accumulating them instead in their lysosomes.  Thus, macrophages turn into dysfunctional Gaucher cells and abnormally secrete inflammatory signals. The deficiency of glucocerebrosidase in Type I Gaucher's disease is only partial and in most cases caused by a mutation  replacing asparagine with serine in the 370^th residue of the protein sequence. The deficiency of the mutant enzyme can be compensated by injection of an exogenous replacement and drastically improve the prognosis for patients with type I Gaucher disease. Prior to the approval of taliglucerase alfa, imiglucerase and velaglucerase alfa were already available ERTs for type I Gaucher's disease. The graphic below illustrates the reaction catalyzed by β-glucocerebrosidase and ERTs. The enzyme classification code for β-glucocerebrosidase is 3.2.1.45.


 Taliglucerase alfa is a monomeric glycoprotein containing 4 N- linked glycosylation sites and has a molecular weight of 60,8 kDa. The recombinant enzyme differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is decorated with mannose-terminated oligosaccharide chains that are specifically recognized by macrophage receptors and assist in 'homing' the enzyme to its target cells.

Taliglucerase alfa is the first ERT expressed in plant cells (carrot root cells), not mammalian cells. Cultures of plant cells are more cost-effective for the expression of recombinant enzymes. 

Crystal structure of the human glucocerebrosidase (PDBe 1ogs).

The recommended dose is 60 Units/kg of body weight administered once every 2 weeks as a 60-120 minute intravenous infusion. A Unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. Adverse effects include pharyngitis, headache, arthralgia, flu and back pain.

Taliglucerase alfa is marketed by Pfizer and Protalix under the brand name Elelyso. 

The full prescribing information can be found here.