Enzyme replacement therapy

Enzyme Replacement Therapy (ERT) is a medical treatment approach targeting congenital enzyme deficiencies. It makes use of purified enzyme preparations sourced from human, animal, or recombinant (genetically engineered) origins. These preparations are typically administered parenterally, most commonly via intravenous infusion.

Indications

The primary candidates for ERT are individuals with rare genetic disorders that cause severe disabilities and increase the risk of premature mortality.

Mechanism of Action

ERT serves to compensate for the absence or inadequacy of a particular enzyme in individuals suffering from inherited enzyme deficiency syndromes. The therapy introduces an externally sourced enzyme, either harvested from human or animal tissues/blood or synthesized through recombinant methods. Often, the introduced enzyme undergoes modifications to enhance its half-life, improve its potency, increase its resistance to degradation, or to target a specific organ, tissue, or cellular structure.

Examples of ERT

Alpha-1-Antitrypsin deficiency: The earliest success stories in ERT pertained to A1AT deficiency, which was treated using purified human A1AT derived from plasma. This deficiency, leading to early-onset emphysema, results from a lack of leukocyte elastase inhibitor, causing continuous pulmonary damage. The therapy demonstrated its efficacy, especially among patients showing early or intermediate pulmonary dysfunction signs. Notably, no instances of viral hepatitis were reported, even though the therapy derived from human plasma.

Gaucher disease: Gaucher disease arises from an inherited deficiency of lysosomal acid β-glucocerebrosidase. This leads to substrate buildup (like glucocerebroside) within lysosomes. The primary affected areas are the liver, spleen, and bone. Initial treatments employed glucocerebrosidase extracted from placental tissue, modified for macrophage-specific uptake and lysosome delivery. However, the current standard employs recombinant forms of glucocerebrosidase for treating type 1 Gaucher disease.

Other Genetic Conditions Treated with ERT

ERT has expanded to address multiple enzyme deficiency syndromes. Some notable diseases include:

• Adenosine deaminase deficiency
• Lysosomal acid lipase deficiency
• Fabry disease
• Pompe disease
• Hurler syndrome
• Hunter syndrome

Other rare mucopolysaccharidoses forms A comprehensive table enumerating approved enzymes for ERT in the U.S. – including their first approval year, generic and brand names, and the associated disease – provides an overview of its widespread applications.

Side Effects

While most patients tolerate both natural purified and recombinant enzymes, potential side effects include:

• Localized infusion reactions
• Hypersensitivity responses, which may manifest as rash, fever, hypotension, bronchospasm, angioneurotic edema, anaphylaxis, or even cardio-pulmonary collapse.

It's noteworthy that hypersensitivity reactions are generally more severe in patients completely lacking the enzyme. Mild reactions often subside over time and may be preventable through premedication with antipyretics, antihistamines, 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