Enzyme replacement therapy

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Information about Enzyme replacement therapy

Enzyme replacement therapy refers to treatment of congenital enzyme deficiencies using purified human, animal or recombinant enzyme preparations. The enzymes are given parenterally, usually by intravenous infusion.

Liver safety of Enzyme replacement therapy

The diseases treated are generally rare genetic disorders which lead to severe disability and premature death.

Mechanism of action of Enzyme replacement therapy

Enzyme replacement therapy is typically used to replace a missing or deficient enzyme in a person with an inherited enzyme deficiency syndrome. The missing enzyme is replaced by infusions of an enzyme that is purified from human or animal tissue or blood or produced by novel recombinant techniques. Typically, the enzyme is modified to allow for a longer half-life, more potent activity, resistance to degradation or targeting to a specific organ, tissue or cell type.

Enzyme replacement therapy for alpha-1-antitrypsin (A1AT) deficiency

The first successful enzyme replacement therapies were for alpha-1-antitrypsin (A1AT) deficiency using plasma derived purified human A1AT. A1AT deficiency is associated with early onset emphysema attributed to the lack of leukocyte elastase inhibitor which leads to progressive pulmonary damage. Small prospective studies suggested a benefit from augmentation therapy, raising the levels of A1AT in serum by infusing the enzyme purified from human serum. This therapy was eventually shown to be beneficial, particularly in patients with early or intermediate pulmonary dysfunction and was quite safe, without the occurrence of viral hepatitis, despite being prepared from human plasma.

Enzyme replacement therapy in Gaucher disease

A second form of successful enzyme replacement therapy was established for Gaucher disease, an inherited deficiency of lysosomal acid β-glucocerebrosidase that leads to accumulation of the substrate (glucocerebroside and its other breakdown products such as ceramide) in lysosomes. The major tissues affected are liver, spleen and bone. The glucocerebrosidase was initially prepared from placental tissue and was modified to allow its specific uptake by macrophages and delivery into lysosomes. Subsequently, recombinant forms of glucocerebrosidase have been developed and now constitute the standard of care for type 1 Gaucher disease.

Genetic diseases treated with enzyme replacement therapy

Subsequently, similar or related approaches have been taken to treat other enzyme deficiency syndromes such as adenosine deaminase deficiency, lysosomal acid lipase deficiency, Fabry disease, Pompe disease, Hurler and Hunter syndrome and several of the rarer forms of mucopolysaccharidoses. A list of enzymes approved for use in enzyme replacement therapy in the United States, the year of first approval, the generic and brand names of the product and the disease for which they are used are given in the Table.

Side effects of Enzyme replacement therapy

Natural purified and recombinant enzymes are generally well tolerated with minimal systemic adverse reactions. The usual major reactions to enzyme replacement therapy are local infusion reactions and hypersensitivity reactions. Hypersensitivity can be a difficult problem, not just in causing allergic symptoms but also in causing inactivity of the enzyme by cross reacting antibodies. Hypersensitivity reactions are generally more common and more severe in patients with total absence of the enzyme, rather than a deficiency or minor amino acid mutation that inactivates the protein. Hypersensitivity reactions can be severe with rash, fever, hypotension, angioneurotic edema, bronchospasm, anaphylaxis and cardio-pulmonary collapse. Most reactions, however, are mild and transient and may be prevented by premedication with antihistamines, antipyretics or corticosteroids.

List of Enzyme replacement therapy

Generic Name Brand Name Enzyme Year Disease
Alpha1-Proteinase inhibitor Prolastin-C Glassia Alpha1-Antitrypsin 2009/2010 A1AT Deficiency
Alglucerase alfa Ceredase* β-Glucocerebrosidase 1991 Gaucher
Imiglucerase Cerezyme β-Glucocerebrosidase 1995 Gaucher
Taliglucerase alfa Elelyso β-Glucocerebrosidase 2012 Gaucher
Velaglucerase alfa VPRIV β-Glucocerebrosidase 2010 Gaucher
Pegademase Adagen Adenosine Deaminase 2000 ADA Deficiency
Agalsidase beta Fabrazyme Alpha-Galactosidase A 2003 Fabry
Alglucosidase alfa Lumizyme Acid alpha-Glucosidase 2010 Pompe
Laronidase Aldurazyme α-L-Iduronidase 2003 Hurler, MPS I
Idursulfase Elaprase Iduronate-2-Sulfatase 2006 Hunter, MPS II
Elosulfase alfa Vimizim N-Acetylgalactosamine-6 Sulfatase 2014 Morquio Snydrome A, MPS IVA
Galsulfase Naglazyme N-Acetylgalactosamine-4 Sulfatase 2005 Maroteaux-Lamy, MPS VI
Sebelipase alfa Kanuma Lysosomal Acid Lipase 2015 Wolman, LAL Deficiency

* Withdrawn from market. MPS=Mucopolysaccharidosis.

genetic disorder agents

cystic fibrosis agents

enzyme replacement therapy

glucosylceramide synthase inhibitors (substrate restriction therapy)

lysosomal acid lipase deficiency agents


homocystinuria agents

Huntington disease agents

Monoclonal Antibodies

Tyrosinemia Agents

Urea Cycle Disorder Agents

Hematologic Agents

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