Gaucher Disease Enzyme Replacement Therapy Assignment Sample

Metabolic Manipulators: Elelyso

Overview of Gaucher Disease Enzyme Replacement Therapy

Elelyso (taliglucerase alfa) has been developed for the enzyme replacement therapy (ERT) of Gaucher's disease (GD), a rare genetic disorder characterized by a lack of β-glucocerebrosidase activity. This enzyme acts naturally on lysosomes and incorporates hydrolysis of glycolipid glucocerebroside obsessed by ceramide and glucose in subjects not pretentious by GD. Tissue macrophages are a prominent cell type that accumulates excess glucocerebroside under these enzyme-free conditions and excessive accumulation of glucocerebrosides in lysosomal segments of monocyte / macrophage cells that produce Gaucher cells: macrophages are loaded with full liprophages and migratory nuclei. The formation of Gaucher cells causes enlargement of the liver and spleen, which can be enormous and lead to bloating. Hepatocellular function is generally well maintained, although transaminases may be slightly elevated. Splenomegaly is associated with hypersplenism and pancytopenia, and anemia and more serious thrombocytopenia.¹

Gaucher's disease is caused by a mutation in the human genome of glucocerebrosidase (hGCD), which results in an inactive enzyme leading to the accumulation of glucocerebroside in the lysosomes of macrophages. Macrophages filled with glycolipid-laden, called Gaucher cells, are originate in the liver, bone marrow, and bone marrow. The oligosaccharide chains in the areas of taliglucerase alpha rpc glycosylation contain the last mannose sugar needed to interact with the mannose receptors present in macrophages.²

The proper dose of taliglucerase alpha is based on body weight and varies from person to person, depending on how well it is tolerated and how much is needed to be effective...³

In healthy subjects, after a single dose of intravenous injection for more than 90 minutes, taliglucerase alfa rpc is immediately removed with an 8-minute life expectancy at a dose of 30 units / kg and 17 minutes at a dose of 60 units per kg. AUCt means 3,608 ng.hr/mL at 30 units per kg and 13474 ng.hr per mL at 60 units per kg.⁴

After one dose and in a stable case the AUC was detected, and the minimum clearance was approximately 30 L / h in units of 30 / kg capacity and 20 L / h in units of 60 / kg capacity.⁵

Research

Adult population

ELELYSO pharmacokinetics were studied in six healthy volunteers and 31 patients with Gaucher's disease. Considering that inclusion rates differed between the two studies, exposure appears to be lower in patients with Gaucher's disease than in healthy subjects. In patients with Gaucher's disease they were treated with 30 or 60 units / kg (N = 29), prescribed pharmacokinetics for the first dose and for 38 weeks.⁶

Pediatric Population

Pharmacokinetics of taliglucerase alfa have been tested in 9 pediatric patients aged 4 to 17 years with Type 1 Gaucher syndrome treated with ELELYSO for 10 to 27 months. Six of the 9 patients were on medication, and 3 patients were switched from glucercerase. In both 30 units / 60 units and 60 units / units, the permissive rates for pediatric patients were the same as for adult patients.⁷

Table 1: clinical trials in specific indication

Diagnosis

Health care professionals usually look at a person's medical history, symptoms, physical examination, and laboratory results to make a diagnosis. The following resources provide information on the diagnosis and diagnosis of the condition.⁸

• Orphanet lists overseas laboratories that provide diagnostic tests for this condition.
• The ACTion (ACT) sheet is available in this case which describes the interim actions to be followed by a health professional where the baby has a positive infant test result. ACT sheets are professionally produced in collaboration with the American College of Medical Genetics.⁸

Treatment

ELELYSO (taliglucerase alpha injection) has been shown to receive long-term enzyme replacement therapy (ERT) in adults with a definite diagnosis of Gaucher-type disease. ELELYSO can also be used in pediatric patients with Gaucher-positive diagnosis, as well as haematological manifestations in pediatric patients with Type 3 Gaucher's diagnosed disease.⁹

Policy

ELELYSO is produced by the practical technology of DNA using plant culture. Purified taliglucerase alpha is a monomeric glycoprotein containing 4 glycosylation sites linked. Taliglucerase alpha differs from traditional human glucocerebrosidase by two amino acids in the N terminal up to 7 amino acids in the C terminal. These chains eliminating the mannose oligosaccharide of taliglucerase alpha are specifically detected by endocytic carbohydrate receptors in macrophages, cells that collect lipid in Gaucher disease. ELELYSO is offered as a sterile, non-pyrogenic, and lyophilized product. The composition of each 200 vial unit is D-mannitol polysorbate 80, sodium citrate, and taliglucerase alpha. Citric acid can be added to adjust the pH during processing.¹⁰

References for Gaucher Disease Enzyme Replacement Therapy

Charrow J. Enzyme replacement therapy for Gaucher disease. Expert Opion Bil 2009:9(1):121-31.

Hollak CEM, Maas M, Aerts JM. Clinically relevant therapeutic endpoints in type I Gaucher disease. J Inherit Metab Dis 2001;24 Suppl 2:97-105.

Hollak CE, Maas M, et al. Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher disease. Blood Cells Mol Dis. 2001;27(6):1005-12.

Maas M, Hollak CE, Akkerman EM, et al. Quantification of skeletal involvement in adults with type I Gaucher’s disease: fat fraction measured by Dixon quantitative chemical shift imaging as a valid AJR Am J Roentgenol 2002;179(4):961-5.

Maas M, Poll LW, Terk MR. Imaging and quantifying skeletal involvement in Gaucher disease. Br J Radiol 2002;75 Suppl 1:A13-24.

Sato Y, Beutler E. Binding, internalization, and degradation of mannose-terminated glucocerebrosidase by macrophages. J Clin Invest. 1993;91(5):1909–1917

Shaaltiel, Y., D. Bartfeld, et al. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. Plant Biotechnol J. 2007;5(5):579-590.

Vellodi A, Tylki-Szymanska A, et al Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis. 2009;32(5):660-4.

van Dussen L, Zimran A, Akkerman EM, Aerts JM, Petakov M, Elstein D, Rosenbaum H, Aviezer D, Brill-Almon E, Chertkoff R, Maas M, Hollak CE. Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease. Blood Cells Mol Dis. 2013 Mar;50(3):206-11.

Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, Solorio-Meza SE, Amato D, Duran G, Giona F, Heitner R, Rosenbaum H, Giraldo P, Mehta A, Park G, Phillips M, Elstein D, Altarescu G, Szleifer M, Hashmueli S, Aviezer D. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase,

taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011 Nov 24;118(22):5767-73.

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