GLA (gene)

Defects in human α-GAL result in Fabry disease, a rare lysosomal storage disorder and sphingolipidosis that results from a failure to catabolize α-D-galactosyl glycolipid moieties.{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2717|title=Entrez Gene: GLA galactosidase, alpha}} Characteristic features include episodes of pain in hands and feet (acroparesthesia), dark red spots on skin (angiokeratoma), decreased sweating (hypohidrosis), decreased vision (corneal opacity), gastrointestinal problems, hearing loss, tinnitus, etc.. Complications may be life-threatening and may include progressive kidney damage, heart attack, and stroke. This disease may have late onset and only affect the heart or kidneys.{{Cite web|url=https://ghr.nlm.nih.gov/condition/fabry-disease|title=Fabry disease |work =Genetics Home Reference|access-date=9 March 2019}}

Fabry disease is an X-linked disease, affecting 1 in 40,000 males. However, unlike other X-linked diseases, this condition also creates significant medical problems for females carrying only 1 copy of the defective GLA gene. These women may experience many classic symptoms of the disorder including cardiac and kidney problems. However, a small number of females carrying only one copy of the mutated GLA gene never shows any symptoms of Fabry disease.{{cn|date=October 2023}}

File:Globotriaosylceramide.svg

Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme. α-GAL is a lysosomal protein responsible for breaking down globotriaosylceramide, a fatty substance stored various types of cardiac and renal cells.{{cite book | vauthors = Ronco C, Bellomo R, Bellasi A | chapter = Chapter 115 - Cardiorenal Syndrome Type 5 | veditors = Ronco C, Bellomo R, Kellum JA, Bellasi A |title=Critical Care Nephrology | edition = Third |publisher= Elsevier |year=2019|isbn=978-0-323-44942-7 |pages=704–711.e2 | doi = 10.1016/B978-0-323-44942-7.00115-1 | s2cid = 86482134 }} When globotriaosylceramide is not properly catabolized, it is accumulated in cells lining blood vessels in the skin, cells in the kidney, heart and nervous system. As a result, signs and symptoms of Fabry disease begin to manifest.

There are three treatment options for Fabry disease: recombinant enzyme replacement therapy, pharmacological chaperone therapy, and organ specific treatment.

RERT was approved as a treatment for Fabry disease in the United States in 2003.{{cite journal | vauthors = Schiffmann R, Kopp JB, Austin HA, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO | title = Enzyme replacement therapy in Fabry disease: a randomized controlled trial | journal = JAMA | volume = 285 | issue = 21 | pages = 2743–9 | date = June 2001 | pmid = 11386930 | doi = 10.1001/jama.285.21.2743 | doi-access = free }}{{cite journal | vauthors = Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ | title = Safety and efficacy of recombinant human α-galactosidase A replacement therapy in Fabry's disease | journal = The New England Journal of Medicine | volume = 345 | issue = 1 | pages = 9–16 | date = July 2001 | pmid = 11439963 | doi = 10.1056/nejm200107053450102 | url = http://dare.uva.nl/personal/pure/en/publications/safety-and-efficacy-of-recombinant-human-alphagalactosidase-a-replacement-therapy-in-fabrys-disease(b4b79813-d3b4-404f-b9b6-1d6e3952bfcc).html | doi-access = free }}{{cite journal | vauthors = Desnick RJ, Schuchman EH | title = Enzyme replacement and enhancement therapies: lessons from lysosomal disorders | journal = Nature Reviews. Genetics | volume = 3 | issue = 12 | pages = 954–66 | date = December 2002 | pmid = 12459725 | doi = 10.1038/nrg963 | s2cid = 11492320 }}

Two recombinant enzyme replacement therapies are available to functionally compensate for α-galactosidase deficiency. Agalsidase α and β are both recombinant forms of the human α-galactosidase A enzyme and both have the same amino acid sequence as the native enzyme. Agalsidase α and β differ in the structures of their oligosaccharide side chains.{{cite journal | vauthors = Fervenza FC, Torra R, Warnock DG | title = Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease | journal = Biologics: Targets and Therapy | volume = 2 | issue = 4 | pages = 823–43 | date = December 2008 | pmid = 19707461 | pmc = 2727881 | doi = 10.2147/btt.s3770 |doi-access=free }}

In Fabry disease patients, 88% percent of patients develop IgG antibodies towards the injected recombinant enzyme, as it is foreign to their immune system. One suggested approach to solving this problem involves converting the paralogous enzyme α-NAGAL (NAGA) into one that has with α-GAL activity. Because patients still have a functional NAGA gene, their immune system will not produce NAGA antibodies.{{cite journal | vauthors = Tomasic IB, Metcalf MC, Guce AI, Clark NE, Garman SC | title = Interconversion of the specificities of human lysosomal enzymes associated with Fabry and Schindler diseases | journal = The Journal of Biological Chemistry | volume = 285 | issue = 28 | pages = 21560–6 | date = July 2010 | pmid = 20444686 | doi = 10.1074/jbc.M110.118588 | pmc = 2898384 | doi-access = free }}

The pharmaceutical company Shire manufactures agalsidase alfa (INN) under the brand name Replagal as a treatment for Fabry disease,{{cite journal | vauthors = Keating GM | title = Agalsidase alfa: a review of its use in the management of Fabry disease | journal = BioDrugs | volume = 26 | issue = 5 | pages = 335–54 | date = October 2012 | pmid = 22946754 | doi = 10.2165/11209690-000000000-00000 }} and was granted marketing approval in the EU in 2001.{{cite web | url = http://www.fiercebiotech.com/press-releases/shire-submits-biologics-license-application-bla-replagal-u-s-food-and-drug-administra | title = Shire Submits Biologics License Application (BLA) for REPLAGAL with the U.S. Food and Drug Administration (FDA) | date = 22 December 2009 | publisher = FierceBiotech }} FDA approval was applied for the United States.{{cite web|url=https://www.npr.org/blogs/health/2010/08/04/128973687/with-a-life-saving-medicine-in-short-supply-patients-want-patent-broken|title=With A Life-Saving Medicine In Short Supply, Patients Want Patent Broken|website=NPR.org |access-date=2 September 2010|date=4 August 2010| archive-url= https://web.archive.org/web/20100914063356/http://www.npr.org/blogs/health/2010/08/04/128973687/with-a-life-saving-medicine-in-short-supply-patients-want-patent-broken | archive-date= 14 September 2010 | url-status= live}} However, in 2012, Shire withdrew their application for approval in the United States citing that the agency will require additional clinical trials before approval.{{cite web|url=http://www.pharmatimes.com/article/12-03-15/Shire_withdraws_Replagal_in_USA_as_FDA_wants_more_trials.aspx |title=Shire withdraws Replagal in USA as FDA wants more trials |author=Grogan K |publisher=PharmaTimes |date=15 March 2012 |url-status=dead |archive-url=https://web.archive.org/web/20140819130944/http://www.pharmatimes.com/article/12-03-15/Shire_withdraws_Replagal_in_USA_as_FDA_wants_more_trials.aspx |archive-date=19 August 2014 }}

{{Infobox drug

| drug_name = Agalsidase beta

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| tradename = Fabrazyme

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| legal_US_comment = {{cite web | title=Fabrazyme- agalsidase beta injection, powder, lyophilized, for solution | website=DailyMed | date=23 February 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=988513ab-b06f-4dd0-93f7-d2d4531dcce4 | access-date=24 March 2024}}

| legal_EU = Rx-only

| legal_EU_comment = {{cite web | title=Fabrazyme EPAR | website=European Medicines Agency | date=8 August 2000 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/fabrazyme | access-date=15 May 2024}}

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The pharmaceutical company Genzyme produces synthetic agalsidase beta (INN) under the brand name Fabrazyme for the treatment of Fabry disease.

File:Chaperones.png

Fabry patients who display neurological symptoms cannot receive RERT because recombinant enzymes cannot normally pass the blood-brain barrier. Thus, a more suitable alternative treatment is used: pharmacological chaperone therapy.{{cn|date=October 2023}}

It has been shown that more potent competitive inhibitors of an enzyme can act as a more powerful chemical chaperone for the corresponding mutant enzyme that fails to maintain proper folding and conformation, despite its intact active site. These chemical chaperones bind to the active site of the mutant enzyme, which can help promote proper folding and stabilize the mutant enzyme. Thus, this results in functional mutant enzymes that will not be degraded via the ubiquitin-proteasome pathway.{{cn|date=October 2023}}

1-Deoxygalactonojirimycin (DGJ) has been shown to be both a potent competitive inhibitor of α-GAL and an effective chaperone to for Fabry disease, increasing intracellular α-GAL's activity by 14-fold.{{cite journal | vauthors = Asano N, Ishii S, Kizu H, Ikeda K, Yasuda K, Kato A, Martin OR, Fan JQ | title = In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives | journal = European Journal of Biochemistry | volume = 267 | issue = 13 | pages = 4179–86 | date = July 2000 | pmid = 10866822 | doi = 10.1046/j.1432-1327.2000.01457.x | doi-access = free }}{{cite journal | vauthors = Fan JQ, Ishii S, Asano N, Suzuki Y | title = Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor | journal = Nature Medicine | volume = 5 | issue = 1 | pages = 112–5 | date = January 1999 | pmid = 9883849 | doi = 10.1038/4801 | s2cid = 13193351 }}

α-GAL, known as B-zyme in this context, has also demonstrated its ability to convert human blood group B to human blood group O, which can be transfused to patients of all blood types in the ABO blood group categorization. The current B-zyme used comes from Bacteroides fragilis.{{cite journal | vauthors = Liu QP, Sulzenbacher G, Yuan H, Bennett EP, Pietz G, Saunders K, Spence J, Nudelman E, Levery SB, White T, Neveu JM, Lane WS, Bourne Y, Olsson ML, Henrissat B, Clausen H | title = Bacterial glycosidases for the production of universal red blood cells | journal = Nature Biotechnology | volume = 25 | issue = 4 | pages = 454–64 | date = April 2007 | pmid = 17401360 | doi = 10.1038/nbt1298 | s2cid = 29804004 }} The idea of maintaining a blood supply at healthcare facilities with all non-O units converted to O units is achieved using enzyme-converted to group O technology, first developed in 1982.{{cite journal | vauthors = Goldstein J, Siviglia G, Hurst R, Lenny L, Reich L | title = Group B erythrocytes enzymatically converted to group O survive normally in A, B, and O individuals | journal = Science | volume = 215 | issue = 4529 | pages = 168–70 | date = January 1982 | pmid = 6274021 | doi = 10.1126/science.6274021 | bibcode = 1982Sci...215..168G }}

A blood bank with ECO blood demonstrates the following advantages:{{cite journal | vauthors = Olsson ML, Clausen H | title = Modifying the red cell surface: towards an ABO-universal blood supply | journal = British Journal of Haematology | volume = 140 | issue = 1 | pages = 3–12 | date = January 2008 | pmid = 17970801 | doi = 10.1111/j.1365-2141.2007.06839.x | s2cid = 10668327 | doi-access = free }}

• Compatible with and transfusable to patients of all blood groups
• Reduce the demand for specific ABO blood groups A, B, AB
• Reduce cost of maintaining a blood bank inventory in hospitals
• Reduce blood transfusion reactions due to human error and ABO incompatibility
• Reduce wastage of less needed blood types

File:B to o.png

Red blood cell (RBC) surfaces are decorated with the glycoproteins and glycolipids that have the same basic sequence with terminal sugar α1‐2‐linked fucose linked to the penultimate galactose. This galactose molecule is called the H antigen.{{cite book | vauthors = Watkins WM | title = Advances in Human Genetics 10 | chapter = Biochemistry and Genetics of the ABO, Lewis, and P Blood Group Systems | volume = 10 | pages = 1–136, 379–85 | date = 1980 | pmid = 6156588 | publisher = Springer US | isbn = 9781461582908 | doi = 10.1007/978-1-4615-8288-5_1 }}{{cite journal | vauthors = Oriol R, Le Pendu J, Mollicone R | title = Genetics of ABO, H, Lewis, X and related antigens | journal = Vox Sanguinis | volume = 51 | issue = 3 | pages = 161–71 | date = 1986 | pmid = 2433836 | doi = 10.1111/j.1423-0410.1986.tb01946.x | doi-access = free }}{{cite journal | vauthors = Clausen H, Hakomori S | title = ABH and related histo-blood group antigens; immunochemical differences in carrier isotypes and their distribution | journal = Vox Sanguinis | volume = 56 | issue = 1 | pages = 1–20 | date = 1989 | pmid = 2464874 | doi = 10.1159/000460912 }} Blood type A, B, AB, and O differ only in the sugar (red molecule in the illustration) linked with the penultimate galactose. For blood type B, this linked sugar is an α-1‐3‐linked galactose. Using α-GAL, this terminal galactose molecule can be removed, converting RBC to type O.

α-GAL derived from the mold Aspergillus niger is an active ingredient in products marketed to reduce stomach gas production after eating foods known to cause gas. It is optimally active at 55 °C, after which its half-life is 120 minutes.{{cite journal | vauthors = Patil AG, K PK, Mulimani VH, Veeranagouda Y, Lee K | title = α-Galactosidase from Bacillus megaterium VHM1 and its application in removal of flatulence-causing factors from soymilk | journal = Journal of Microbiology and Biotechnology | volume = 20 | issue = 11 | pages = 1546–54 | date = November 2010 | pmid = 21124061 | doi = 10.4014/jmb.0912.12012 | doi-broken-date = 11 November 2024 | s2cid = 24801055 }}

Commercial products with α-galactosidase include:

• Beano
• CVS BeanAid
• Enzymedica's BeanAssist
• Gasfix
• Bloateez (in India as Cogentrix)

{{Reflist}}

• {{MeshName|alpha-Galactosidase}}
• {{UCSC gene info|GLA}}

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