Stanford BIO 118 - Enzyme Replacement Therapy

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Enzyme Replacement TherapyCarolyn SinowBiochem 118Professor BrutlagDecember, 2 2010Lysosomal Storage Diseases (LSD)Lysosome = organelle responsible for catabolyzing macromoleculesCharacterized by deficiency of lysosomal enzymeGroup of over 40 diseasesMost are autosomal recessiveCombined incidence of 1:6500 – 7500 live birthsEnzyme Replacement Therapy (ERT)Cultivate missing enzyme outside the human body and then administer it to patients as treatmentCan be used for diseases besides LSDFirst suggested in 1960s by Roscoe BradyTreats the cause, not just the symptomsCreation of ERTCurrently ERT for 6 Lysosomal storage diseasesPlasmidChinese Hamster Ovary CellsPurificationAnimal modelsClinical TrialsGaucher’s Disease1st developed ERTMost common of the lysosomal storage diseasesDeficient enzyme: Glucocerebrodase (catabolyzes glucoceramide)Affects spleen, liver & bone marrow3 clinical subtypesGaucher Disease type 1: lethal by 2 years oldCerezymeERT reverses pathologies  near normal liveshttp://geneticpeople.com/?p=276Fabry DiseaseX-linked inheritanceDeficient enzyme: α-galactosidase (catabolyzes globotriaosylceramide)Symptoms:Usually begin in adolescenceAcroparesthesiasPain and gastrointestinal problemsFabrazymePrevents but does not reverse damagePain remainsPompe DiseaseA.k.a. Glycogen storage disease type IIDeficient enzyme: α-glucosidaseOnset infant – adulthoodSkeletal muscle problemsMyozymeERT prolongs infant life, increases motor abilitiesClinical 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 diseasesGlycosaminoglycans accumulate3 types have treatmentMPS IHurler or Hurler-Scheie syndromeα-L-iduronidaseMPS IIHunter syndromeX-linked inheritanceIduronate sulfataseMPS VIMaroteaux-Lamy syndromeArylsulfataseMucopolysaccharidosesCommon symptoms: coarse facies, deafness, cardiac disease, delayed development, neurologic problems (I & VI)Bone marrow transplant (Hurler)Enzyme replacement therapiesAldurazyme (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 diseasesCan correct symptoms, not diseaseCystic fibrosis – has problems with pancreatic ducts that prevents enzymes from reaching gastrointestinal tractPancreatitisPancreatic and periampullary cancerShortcomings of ERTAdmistered via IV once every 2 weeksInfusions last 2 – 6 hoursSide EffectsAllergy symptoms, respiratory distressLong term effects not yet knownGaucher’s: treated for 15 – 20 years with no severe side effectsAntibody responsesIgG – binds to drugs  allergy symptomsIgE – increased risk of anaphylactic reactionCost = $200,000 - $300,000 per yearCan max out health insurance in 2 – 5 yearsAffects employmentSourcesLaurie, 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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Stanford BIO 118 - Enzyme Replacement Therapy

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