Enzyme replacement therapy

Enzyme replacement therapy
Enzyme replacement therapy
Other names	ERT
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Last updated January 01, 2024

Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body.^[1] Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.^[1]

ERT is available for some lysosomal storage diseases: Gaucher disease, Fabry disease, MPS I, MPS II (Hunter syndrome), MPS VI and Pompe disease.^[1] ERT does not correct the underlying genetic defect, but it increases the concentration of the enzyme that the patient is lacking.^[1] ERT has also been used to treat patients with severe combined immunodeficiency (SCID) resulting from an adenosine deaminase deficiency (ADA-SCID).^[2]

Other treatment options for patients with enzyme or protein deficiencies include substrate reduction therapy, gene therapy, and bone-marrow derived stem cell transplantation. ^[1]^[3]^[4]

History

ERT was developed in 1964 by Christian de Duve and Roscoe Brady.^[1]^[5] Leading work was done on this subject at the Department of Physiology at the University of Alberta by Mark J. Poznansky and Damyanti Bhardwaj, where a model for enzyme therapy was developed using rats.^[6] ERT was not used in clinical practice until 1991, after the FDA gave orphan drug approval for the treatment of Gaucher disease with Alglucerase.^[1] ERTs were initially manufactured by isolating the therapeutic enzyme from human placenta.^[1] 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.^[1]

Medical uses

Lysosomal storage diseases are a group of diseases and a main application of ERT. Lysosomes are cellular organelles that are responsible for the metabolism of many different macromolecules and proteins.^[7] They use enzymes to break down macromolecules, which are recycled or disposed.^[7] As of 2012, there are 50 lysosomal storage diseases, and more are still being discovered.^[8]^[7] These disorders arise because of genetic mutations that prevent the production of certain enzymes used in the lysosomes.^[7] The missing enzyme often leads to a build-up of the substrate 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.^[8] 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.^[2]

ERT has also been successful in treating severe combined immunodeficiency caused by an adenosine deaminase deficiency (ADA-SCID).^[9] This is a fatal childhood disease that requires early medical intervention.^[9] When the enzyme adenosine deaminase is deficient in the body, the result is a toxic build-up of metabolites that impair lymphocyte development and function.^[9] 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.^[9]

Diseases and corresponding enzyme therapies. Information in this table is from pivotal clinical trials.^[1]
Disease	Enzyme	Administration
Fabry disease	Agalsidase beta	IV
Fabry disease	Agalsidase alfa	IV
Gaucher disease	Imiglucerase	IV
Gaucher disease	Taliglucerase alfa	IV
Gaucher disease	Velaglucerase alfa	IV
Gaucher disease type I	Alglucerase	IV
Lysosomal acid lipase deficiency (Wolman disease/CESD)	Sebelipase alfa	IV
MPS I	Laronidase	IV
MPS II	Idursulfase	IV
MPS IVA	Elosulfase alfa	IV
MPS VI	Galsulfase	IV
Pompe disease	Alglucosidase alfa (160L bioreactor)	IV
Pompe disease	Alglucosidase alfa (4000L bioreactor)	IV
Thrombotic thrombocytopenic purpura	Apadamtase alfa	IV

Administration

ERT is administered by IV infusion.^[1]^[9]^[10] Typically, infusions occur every week or every two weeks.^[1] For some types of ERT, these infusions can occur as infrequently as every four weeks.^[1]

Complications

ERT is not a cure for lysosomal storage diseases, and it requires lifelong IV infusions of the therapeutic enzyme.^[10] This procedure is expensive; in the United States, it may cost over $200,000 annually.^[10] The distribution of the therapeutic enzyme in the body (biodistribution) after these IV infusions is not uniform.^[10] 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.^[10] Additionally, the efficacy of ERT is often reduced due to an unwanted immune response against the enzyme, which prevents metabolic function.^[10]

Other treatments for enzyme deficiencies

Substrate reduction therapy is another method for treating lysosomal storage diseases.^[10] In this treatment, the accumulated compounds are inhibited from forming in the body of a patient with a lysosomal storage disease.^[10] The accumulated compounds are responsible for the symptoms of these disorders, and they form via a multi-step biological pathway.^[10] Substrate reduction therapy uses a small molecule to interrupt this multi-step pathway and inhibit the biosynthesis of these compounds.^[10] This type of treatment is taken orally.^[10] It does not induce an unwanted immune response, and a single type of small molecule could be used to treat many lysosomal storage diseases.^[10] Substrate reduction therapy is FDA approved and there is at least one treatment available on the market.^[10]

Gene therapy aims to replace a missing protein in the body through the use of vectors, usually viral vectors.^[11] In gene therapy, a gene encoding for a certain protein is inserted into a vector.^[11] The vector containing the therapeutic gene is then injected into the patient.^[11] 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.^[11] This type of therapy can correct for the missing protein/enzyme in patients with lysosomal storage diseases.^[1]

Hematopoietic stem cell (HSC) transplantation is another treatment for lysosomal storage diseases.^[12] HSCs are derived from bone-marrow.^[13] These cells have the ability to mature into the many cell types that comprise blood, including red blood cells, platelets, and white blood cells.^[13] 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.^[12] This treatment is often used to treat the central nervous system of patients with some lysosomal storage diseases.^[12]

Related Research Articles

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in differing clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

Adenosine deaminase deficiency is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–20% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) after excluding disorders related to inbreeding.

<span class="mw-page-title-main">Alpha-mannosidosis</span> Medical condition

Alpha-mannosidosis is a lysosomal storage disorder, first described by Swedish physician Okerman in 1967. In humans it is known to be caused by an autosomal recessive genetic mutation in the gene MAN2B1, located on chromosome 19, affecting the production of the enzyme alpha-D-mannosidase, resulting in its deficiency. Consequently, if both parents are carriers, there will be a 25% chance with each pregnancy that the defective gene from both parents will be inherited, and the child will develop the disease. There is a two in three chance that unaffected siblings will be carriers. In livestock alpha-mannosidosis is caused by chronic poisoning with swainsonine from locoweed.

Glycogen storage disease type II, also called Pompe disease, and formerly known as GSD-IIa. It 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 the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

Pyruvate kinase deficiency is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells. Both autosomal dominant and recessive inheritance have been observed with the disorder; classically, and more commonly, the inheritance is autosomal recessive. Pyruvate kinase deficiency is the second most common cause of enzyme-deficient hemolytic anemia, following G6PD deficiency.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders. Another term used to describe these disorders is "enzymopathies". This term was created following the study of biodynamic enzymology, a science based on the study of the enzymes and their products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

A lipid storage disorder is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or, they produce enzymes that do not work properly. Over time, the buildup of fats may cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.

Roscoe Owen Brady was an American biochemist.

Hunter syndrome, or mucopolysaccharidosis type II, is a rare genetic disorder in which large sugar molecules called glycosaminoglycans build up in body tissues. It is a form of lysosomal storage disease. Hunter syndrome is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. Hunter syndrome is the only MPS syndrome to exhibit X-linked recessive inheritance.

Deoxyadenosine triphosphate (dATP) is a nucleotide used in cells for DNA synthesis, as a substrate of DNA polymerase.

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive metabolic disorder which results in immunodeficiency.

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 breakdown and disposal of some large molecule. If residual breakdown through other pathways is insufficient to prevent harmful accumulation, the molecule accumulates in the cell and eventually interferes with normal biological processes. Examples of lysosomal storage disorders include Gaucher's disease, Tay–Sachs disease, Sandhoff disease, and Sanfilippo syndrome.

<span class="mw-page-title-main">Lysosomal acid lipase deficiency</span> Medical condition

Lysosomal acid lipase deficiency is an autosomal recessive inborn error of metabolism that results in the body not producing enough active lysosomal acid lipase (LAL) enzyme. This enzyme plays an important role in breaking down fatty material in the body. Infants, children and adults that have LAL deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other important organs.

Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence, sold under the brand name Strimvelis, is a medication used to treat severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID).

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic disease associated with systemic inflammation and vasculopathy that affects a wide variety of organs in different patients. As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease include but are not limited to recurrent fever, livedoid rash, various cytopenias, stroke, immunodeficiency, and bone marrow failure. Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.

Olipudase alfa, sold under the brand name Xenpozyme, is a medication used for the treatment of non-central nervous system (CNS) manifestations of acid sphingomyelinase deficiency (ASMD) type A/B or type B.

References

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ries, M (2017). "Enzyme replacement therapy and beyond-in memoriam Roscoe O. Brady, M.D. (1923–2016)". Journal of Inherited Metabolic Disease. 40 (3): 343–356. doi:10.1007/s10545-017-0032-8. PMID 28314976. S2CID 31320877.
1 2 Booth, C; Hershfield, M; Notarangelo, L; Buckley, R; Hoenig, M; Mahlaoui, N; Cavazzana-Calvo, M; Aiuti, A; Gaspar, H. B. (2007). "Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006)". Clinical Immunology. 123 (2): 139–47. doi:10.1016/j.clim.2006.12.009. PMID 17300989.
↑ Ries, M (2017). "Enzyme replacement therapy and beyond-in memoriam Roscoe O. Brady, M.D. (1923–2016)". Journal of Inherited Metabolic Disease. 40 (3): 343–356. doi:10.1007/s10545-017-0032-8. PMID 28314976. S2CID 31320877.^{[ verification needed ]}
↑ Ries, M (2017). "Enzyme replacement therapy and beyond-in memoriam Roscoe O. Brady, M.D. (1923–2016)". Journal of Inherited Metabolic Disease. 40 (3): 343–356. doi:10.1007/s10545-017-0032-8. PMID 28314976. S2CID 31320877.^{[ verification needed ]}
↑ Neufeld EF (2006). "Chapter 10: Enzyme replacement therapy – a brief history". In Mehta A, Beck M, Sunder-Plassmann G (eds.). Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis. ISBN 978-1-903539-03-3. PMID 21290685.
↑ Poznansky, M. J. (1984). "Enzyme-albumin polymers. New approaches to the use of enzymes in medicine". Applied Biochemistry and Biotechnology. 10: 41–56. doi:10.1007/BF02783734. PMID 6395807. S2CID 87349537.
1 2 3 4 Weiss, N (2012). "Cross-talk between TRPML1 channel, lipids and lysosomal storage diseases". Communicative & Integrative Biology. 5 (2): 111–113. doi:10.4161/cib.20373. PMC 3376041 . PMID 22808310.
1 2 "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/.
1 2 3 4 5 Tartibi, H. M.; Hershfield, M. S.; Bahna, S. L. (2016). "A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient". Pediatrics. 137 (1): e20152169. doi: 10.1542/peds.2015-2169 . PMID 26684479.
1 2 3 4 5 6 7 8 9 10 11 12 13 Coutinho, M. F.; Santos, J. I.; Alves, S (2016). "Less is More: Substrate Reduction Therapy for Lysosomal Storage Disorders". International Journal of Molecular Sciences. 17 (7): 1065. doi: 10.3390/ijms17071065 . PMC 4964441 . PMID 27384562.
1 2 3 4 "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.
1 2 3 Biffi, A (2016). "Gene therapy for lysosomal storage disorders: A good start". Human Molecular Genetics. 25 (R1): R65–75. doi: 10.1093/hmg/ddv457 . PMID 26604151.
1 2 Domen, J., Wagers, A., & Weissman, I. "Bone Marrow (Hematopoietic) Stem Cells." April 19, 2017, from https://stemcells.nih.gov/info/Regenerative_Medicine/2006chapter2.htm Archived 2021-05-15 at the Wayback Machine .