Enzyme replacement therapy

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

• ivacaftor
• lumacaftor
• cystinosis agents
• cysteamine

enzyme replacement therapy

• gaucher disease agents
  • glucocerebrosidase (enzyme replacement therapy)
  • imiglucerase, taliglucerase alfa, velaglucerase alfa

glucosylceramide synthase inhibitors (substrate restriction therapy)

• eliglustat, miglustat

lysosomal acid lipase deficiency agents

• sebelipase alfa

miscellaneous

• agalsidase beta, alglucosidase alfa, alpha1-proteinase inhibitor, elosulfase alfa, galsulfase, idursulfase, laronidase, pegademase

homocystinuria agents

• betaine

Huntington disease agents

• Tetrabenazine

• • Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors
    • Deutetrabenazine, Tetrabenazine, Valbenazine

Monoclonal Antibodies

• Burosumab

Tyrosinemia Agents

• Nitisinone

Urea Cycle Disorder Agents

• Carglumic acid, Lactulose, Phenylbutyrate, Rifaximin, Sodium benzoate

Hematologic Agents

• Eculizumab, Emapalumab, Emicizumab, Lanadelumab, Ravulizumab

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