Enzyme replacement therapy (ERT) is a medical treatment which replaces an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme. ERT is available for some lysosomal storage diseases: Gaucher disease,

Fabry disease Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...

, MPS I, MPS II (Hunter syndrome), MPS VI and

Pompe disease Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of th ...

. ERT does not correct the underlying genetic defect, but it increases the concentration of the enzyme that the patient is lacking. ERT has also been used to treat patients with severe combined immunodeficiency (SCID) resulting from an adenosine deaminase deficiency (

ADA-SCID Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immun ...

). Other treatment options for patients with enzyme or protein deficiencies include

substrate reduction therapy Substrate reduction therapy offers an approach to treatment of certain metabolic disorders, especially glycogen storage diseases and lysosomal storage disorders. In a storage disorder, a critical failure in a metabolic pathway prevents cellular br ...

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...

, and bone-marrow derived stem cell transplantation.

History

ERT was developed in 1964 by Christian de Duve and

Roscoe Brady Roscoe Owen Brady (October 11, 1923 – 13 June 2016) was an American biochemist. He attended the Pennsylvania State University and obtained his M.D. degree from Harvard Medical School in 1947. He interned at the Hospital of the University of P ...

. Leading work was done on this subject at the Department of Physiology at the

University of Alberta The University of Alberta, also known as U of A or UAlberta, is a public research university located in Edmonton, Alberta, Canada. It was founded in 1908 by Alexander Cameron Rutherford,"A Gentleman of Strathcona – Alexander Cameron Rutherfor ...

by Mark J. Poznansky and Damyanti Bhardwaj, where a model for enzyme therapy was developed using rats. ERT was not used in clinical practice until 1991, after the FDA gave

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

approval for the treatment of Gaucher disease with Alglucerase. ERTs were initially manufactured by isolating the therapeutic enzyme from human placenta. The FDA has approved ERTs that are derived from other human cells, animal cells (i.e. Chinese hamster ovary cells, or CHO cells), and plant cells.

Medical uses

Lysosomal storage diseases are fatal group of diseases and a main application of ERT.

Lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

s are cellular organelles that are responsible for the metabolism of many different macromolecules and proteins. They use enzymes to break down

macromolecule A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

s, which are recycled or disposed. As of 2012, there are 50 lysosomal storage diseases, and more are still being discovered."Lysosomal Storage Disorders – NORD (National Organization For Rare Disorders)". ''NORD (National Organization for Rare Disorders)''. Apr. 2017, from https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/. These disorders arise because of genetic mutations that prevent the production of certain enzymes used in the lysosomes. The missing enzyme often leads to a build-up of the

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...

within the body. This can result in a variety of symptoms, many of which are severe and can affect the skeleton, brain, skin, heart, and the central nervous system. Increasing the concentration of the missing enzyme within the body has been shown to improve the body's normal cellular metabolic processes and reduce substrate concentration in the body. ERT has also been successful in treating severe combined immunodeficiency caused by an adenosine deaminase deficiency (ADA-SCID). This is a fatal childhood disease that requires early medical intervention. When the enzyme adenosine deaminase is deficient in the body, the result is a toxic build-up of metabolites that impair

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

development and function. Many ADA deficient children with SCID have been treated with the polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme. This is a form of ERT that has resulted in healthier, longer lives for patients with ADA-SCID.

Administration

ERT is administered by IV infusion. Typically, infusions occur every week or every two weeks. For some types of ERT, these infusions can occur as infrequently as every four weeks.

Complications

ERT is not a cure for lysosomal storage diseases, and it requires lifelong IV infusions of the therapeutic enzyme. This procedure is expensive; in the United States, it may cost over $200,000 annually. The distribution of the therapeutic enzyme in the body ( biodistribution) after these IV infusions is not uniform. The enzyme in less available to certain areas in the body, like the bones, lungs, brain. For this reason, many symptoms of lysosomal storage diseases remain untreated by ERT, especially neurological symptoms. Additionally, the efficacy of ERT is often reduced due to an unwanted immune response against the enzyme, which prevents metabolic function.

Other treatments for enzyme deficiencies

Substrate reduction therapy is another method for treating lysosomal storage diseases. In this treatment, the accumulated compounds are inhibited from forming in the body of a patient with a lysosomal storage disease. The accumulated compounds are responsible for the symptoms of these disorders, and they form via a multi-step biological pathway. Substrate reduction therapy uses a small molecule to interrupt this multi-step pathway and inhibit the biosynthesis of these compounds. This type of treatment is taken orally. It does not induce an unwanted immune response, and a single type of small molecule could be used to treat many lysosomal storage diseases. Substrate reduction therapy is FDA approved and there is at least one treatment available on the market. Gene therapy aims to replace a missing protein in the body through the use of vectors, usually

viral vector Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (''in vivo'') or in cell culture (''in vitro''). Viruses have evolved specialized molecul ...

s."How does gene therapy work? - Genetics Home Reference." U.S. National Library of Medicine. April 18, 2017, from https://ghr.nlm.nih.gov/primer/therapy/procedures. In gene therapy, a gene encoding for a certain protein is inserted into a vector. The vector containing the therapeutic gene is then injected into the patient. Once inside the body the vector introduces the therapeutic gene into host cells, and the protein encoded by the newly inserted gene is then produced by the body's own cells. This type of therapy can correct for the missing protein/enzyme in patients with lysosomal storage diseases. Hematopoietic stem cell (HSC) transplantation is another treatment for lysosomal storage diseases. HSCs are derived from bone-marrow.Domen, J., Wagers, A., & Weissman, I. "Bone Marrow (Hematopoietic) Stem Cells." April 19, 2017, from https://stemcells.nih.gov/info/Regenerative_Medicine/2006chapter2.htm. These cells have the ability to mature into the many cell types that comprise blood, including red blood cells, platelets, and white blood cells. Patients with enzyme deficiencies often undergo HSC transplantations in which HSCs from a healthy donor are injected. This treatment introduces HSCs that regularly produce the deficient enzyme since they have normal metabolic function. This treatment is often used to treat the central nervous system of patients with some lysosomal storage diseases.

History

Medical uses

Administration

Complications

Other treatments for enzyme deficiencies

See also

References

Further reading