Enzyme Replacement TherapyCarolyn SinowBiochem 118Professor BrutlagDecember, 2 2010Lysosomal Storage Diseases (LSD)Lysosome = organelle responsible for catabolyzing macromoleculesCharacterized by deficiency of lysosomal enzymeGroup of over 40 diseasesMost are autosomal recessiveCombined incidence of 1:6500 – 7500 live birthsEnzyme Replacement Therapy (ERT)Cultivate missing enzyme outside the human body and then administer it to patients as treatmentCan be used for diseases besides LSDFirst suggested in 1960s by Roscoe BradyTreats the cause, not just the symptomsCreation of ERTCurrently ERT for 6 Lysosomal storage diseasesPlasmidChinese Hamster Ovary CellsPurificationAnimal modelsClinical TrialsGaucher’s Disease1st developed ERTMost common of the lysosomal storage diseasesDeficient enzyme: Glucocerebrodase (catabolyzes glucoceramide)Affects spleen, liver & bone marrow3 clinical subtypesGaucher Disease type 1: lethal by 2 years oldCerezymeERT reverses pathologies near normal liveshttp://geneticpeople.com/?p=276Fabry DiseaseX-linked inheritanceDeficient enzyme: α-galactosidase (catabolyzes globotriaosylceramide)Symptoms:Usually begin in adolescenceAcroparesthesiasPain and gastrointestinal problemsFabrazymePrevents but does not reverse damagePain remainsPompe DiseaseA.k.a. Glycogen storage disease type IIDeficient enzyme: α-glucosidaseOnset infant – adulthoodSkeletal muscle problemsMyozymeERT prolongs infant life, increases motor abilitiesClinical trials still in process for late onset Pompehttp://www.fightpompe.com/article/45/fight-pompe-around-the-worldhttp://www.joemcdowellphotography.com/Haley/Haley/1903403_Mpc3n/3/97982714_W9w3V#97982714_W9w3VMucopolysaccharidoses (MPS)Group of 6 diseasesGlycosaminoglycans accumulate3 types have treatmentMPS IHurler or Hurler-Scheie syndromeα-L-iduronidaseMPS IIHunter syndromeX-linked inheritanceIduronate sulfataseMPS VIMaroteaux-Lamy syndromeArylsulfataseMucopolysaccharidosesCommon symptoms: coarse facies, deafness, cardiac disease, delayed development, neurologic problems (I & VI)Bone marrow transplant (Hurler)Enzyme replacement therapiesAldurazyme (Hurler) – 2003 Elaprase (Hunter) – 2006 Naglazyme (Maroteaux-Lamy) – 2005 http://www.maroteaux-lamy.com/English/hcp/AboutMPS.aspxhttp://chad-pyper.last-memories.com/?http://www.metabolica.org/start/node/8Hurler Hunter Maroteaux-LamyNon lysosomal storage diseasesCan correct symptoms, not diseaseCystic fibrosis – has problems with pancreatic ducts that prevents enzymes from reaching gastrointestinal tractPancreatitisPancreatic and periampullary cancerShortcomings of ERTAdmistered via IV once every 2 weeksInfusions last 2 – 6 hoursSide EffectsAllergy symptoms, respiratory distressLong term effects not yet knownGaucher’s: treated for 15 – 20 years with no severe side effectsAntibody responsesIgG – binds to drugs allergy symptomsIgE – increased risk of anaphylactic reactionCost = $200,000 - $300,000 per yearCan max out health insurance in 2 – 5 yearsAffects employmentSourcesLaurie, Bailey. "An Overview of Enzyme Replacement Therapy for Lysosomal Storage Diseases." The Online Journal of Issues in Nursing (2006). Web.Stirnemann, Jerome, Anne Boutten, Corine Vincent, and Arsene Mekinian. "Impact of Imiglucerase on the Serum Glycosylated-ferritin Level in Gaucher Disease." Blood Cells, Molecules and Diseases (2010). Print."What Is Enzyme Replacement Therapy?" WiseGEEK: Clear Answers for Common Questions. Web. 02 Dec. 2010. <http://www.wisegeek.com/what-is-enzyme-replacement-therapy.htm>.Imrie, CW, G. Connett, RI Hall, and RM Charnley. "Review Article: Enzyme Supplementation in Cystic Fibrosis, Chronic Pancreatitis, Pancreatic and Periampullary Cancer." Aliment Pharmacol Ther 1st ser. 32 (2010): 1-25.
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