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Enzyme Replacement Therapy

Enzyme Replacement Therapy (ERT) is a medical treatment for lysosomal storage disorders (LSD) that supplies the patient with an enzyme that is lacking or has an incorrect function in the cell. ERTs are given to patients with the intent of improving their quality of life, prolonging their life, and in some cases reversing affects of the LSD.

Diagram of an Enzyme

ERT works by supplying the patient with an enzyme their body is lacking or an enzyme that has an impaired function. This difference in the issues with the enzyme is dependent on the disease type and mutation type of the patient. ERT are usually administered intravenously. The injections of the necessary enzyme supplies the patient with the enzyme their body is missing due to a genetic error in the gene(s) coding for that enzyme. ERT does not eliminate the underlying genetics problems within the patient’s cells it instead alleviates the symptoms and, or slows the progression of the disease by supplying the patient’s body with the enzyme. Normal functioning in the cells is regained because the enzyme being injected into the patient performs the function the mutated enzyme could not perform or was not present to perform. The injected enzyme is then able to break down or properly transport the accumulated substance in the lysosomes.

History:

The idea of enzyme replacement therapy, as a treatment for lysosomal storage disease, was first introduced by Christian de Duve around forty years ago. Duve hypothesized through his experiments that substances that enter the cell are likely to end up in the cell’s lysosomes. This hypothesis led to future experiments which eventually led to the first successful ERT. Brady and colleagues created the first ERT. The LSD that their ERT treated was Gaucher disease. The original treatments were made by collecting the enzyme of interest from human placental cells. Later, human placental cells were replaced by Chinese hamster ovary (CHO) cells as the source of the enzyme of interest. CHO cells produce recombinant enzymes. The enzymes are collected and used in the injections. This method is still used by biotechnology companies to make ERTs.

One of the first studies on ERT was conducted by Desnick et al. In their study they injected patients with alpha-galactosidase A. Their studies showed that the enzymes harvested from the CHO cells improved the condition of the patients. Desnick et al.’s study showed a decrease in the build-ups of globotriaosylceramide in their patients. Schiffmann et al. also performed a randomized study with ERT and observed improvements in lysosomal accumulations, as well. The results of these two trials lead to their approval by the European Union, as well as, approval in the United States.

Disease it is used to treat:

There are various diseases that require ERT as treatment these include ,4):

- Gaucher disease

- Fabry disease

- Pompe disease (GAA deficiency)

- Mucopolysaccharidosis I (MPS I)

- Hurler syndrome

- Hurler-Scheie syndrome

- Scheie syndrome

- Mucopolysaccharidosis II (MPS II)

- Hunter Syndrome

- Mucopolysaccharidosis VI (MPS VI)

- Maroteaux- Lamy Syndrome

- Familial Hypercholesterolemia (HoFH)

Types of ERT:

Each ERT is created for a specific lysosomal storage disorder. This is because each disorder is due to an error in a specific enzyme. Therefore, when the treatments are created they are made with the recombinant version the deficient enzyme of that form of LSD.

ERT have been made and proven successful for many of these LSD, most of which are manufactured by Genzyme.

Treatment Name	Enzyme	Disease (s)
Aldurazyme	Laronidase	Hurler, Hurler-Scheie, certain forms of MPS I, and Scheie syndrome (moderate to severe symptoms)
Cerezyme	Imiglucerase	Type 1 Gaucher disease
Fabrazyme	Algalsidase beta	Fabry disease
Kynamro	Mipomersen sodium	HoFH
Lumizyme	Alglucosidase alfa	Non-infantile Pompe disease (GAA deficiency)
Myozyme	Alglucosidase alfa	Pompe disease (GAA deficiency) Infantile Pompe disease
Thyrogen	Thrypotropin alfa	Thyroid Cancer and Thyroid Surgies (is used in preparation for these and can be taken during chemotherapy)

The information in the above table was obtained from source 6.

Injection of the ERT:

Intravenous Injection of Treatment

Infusions of the ERT usually occur every two weeks and can take any where between two to six hours . These are either performed in a doctor’s office, hospital, or the patient’s home by a visiting nurse or physician. The location depends on a variety of aspects such as, the patients reactions to the injections, how long the patient has been receiving therapies, and the which ERT is being administered.

Side effects:

Many of the side effects associated with ERT are not life threatening and can be treated. However, there are some side effects that are more dangerous but few have been found to be life threatening. The less severe symptoms include itching and, or redness around the area where the IV was inserted, edema, hives, nasal discharge, watery eyes, and itching all over the body, chills, rigors, and fatigue. Slightly more severe symptoms that have been experienced are chest tightness, respiratory distress, and cardiac arrythmia. When reactions like these occur they can be treated through the administering of antihistamines or corticosteroids. If patients have been known to have reactions they can receive treatment before injection with antipyretics or antihistamines, which can reduce or eliminate the post injection symptoms. If reactions do occur when the patient receives an injection doctors take blood and test it to determine if the patient has developed antibodies.