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Pompe's Disease

CHEM 222 Lab Presentation
by

Kate McConnell

on 2 May 2013

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Transcript of Pompe's Disease

Enzyme Replacement Therapy in Pompe's Disease Kate McConnell and Daniele Evangelista The Crowley Family CHEM 232 - Thursday Lab
Spring 2013 Research Strategies Enzyme replacement therapy (ERT) Fig. 1. Imino sugars used in this experiment. What is Pompe's? GSD = Glycogen Storage Disorder (Type II)
GAA = acid alpha-glucosidase Symptoms Exogenous alglucosidase alfa
Myozyme - early-onset
Lumizyme - late-onset MCVIE-MYLIE, A.J., et al, 2008 Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease. Mol Genet Metab 94: 448-455. Fig. 3. Metamorph glycogen analysis of heart and quadriceps tissue from GAA knockout mice administered CHO–GAA, tgGAA, and HP–GAA for four weekly doses of 20, 60, and 100 mg/kg (mean ± SD). Indicates p < 0.05 as compared to vehicle. Fig. 4. Enzyme activity analysis of heart and quadriceps from GAA knockout mice administered CHO–GAA, tgGAA, and HP–GAA for four weekly doses of 20, 60, and 100 mg/kg (mean ± SD). Indicates p < 0.05 as compared to tgGAA and CHO–GAA; #Indicates p < 0.05 as compared to tgGAA and HP–GAA. rhGAA: recombinant human
CHO-GAA: conventional CHO cell-produced form
tgGAA: produced in the milk of transgenic rabbits
HP-GAA: carbohydrate engineered form containing high levels of mannose-6-phosphate Myozyme is Effective During the first 52 weeks of treatment, 7 of 8 patients showed continuous increases in body weight and length (Figure 3), resulting in maintenance or improvement in percentile rankings on the basis of Center for Disease Control/National Center for Health Statistics weight and length growth charts. KISHANI, P.S. et al, 2006 Chinese hamster ovary cell-line derived recombinant human acid alpha-glucosidases in infantile-onset Pompe disease. J Pediatr 149: 89-97. ERT
Improvements/Alternatives? ZHU, Y. et al, 2005 Carbohydrate-remodelled acid a-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice. J Biochem 389: 619-628. neo-rhGAA: modified recombinant human GAA harbouring ~6 synthetic oligosaccharide ligands bearing M6P residues in the optimal configuration for binding the receptor ZHU, Y. et al, 2005 Carbohydrate-remodelled acid a-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice. J Biochem 389: 619-628. YOSHIMIZU, M. et al, 2008 Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human alpha-glucosidase (alglucosidase alpha): Insight into the complex formation mechanism. Clinica Chimica Acta 391: 68-73. Fig. 2. Structural models of the complexes of human acid -glucosidase with imino sugars bound to its active site. a. Amino acid residues of the active-site pocket of human acid -glucosidase involved in the binding with DNJ. The dotted lines denote hydrogen bonds. b. Relation between DNJ and amino acid residues comprising the active-site pocket of the enzyme. c. Surface structure of the active-site pocket and DNJ. d. Surface structure of the active-site pocket and NB-DNJ. NOT a cure, but ERT is currently the most effective treatment we have for Pompe's Disease Enzyme Enhancement
Therapy (EET) ERT in Other Metabolic Diseases Literature Cited and Other References Gaucher Disease
Fabray Disease
Mucopolysaccharidoses
Hypophosphatasia Future Research in the Treatment of Pompe's Gene Therapy Questions?
Comments? Thank you! CHIEN, Y.H. and E.L. HWU, 2007 A review of treatment of Pompe disease in infants. Biologics, 1: 195-201.

KISHANI, P.S. et al, 2006 Chinese hamster ovary cell-line derived recombinant human acid alpha-glucosidases in infantile-onset Pompe disease. J Pediatr 149: 89-97.

LIPINSKI, S.E., 2012 Alglucosidase alfa and Pompe disease: Still going strong? Mol Genet Metab 107: 245-246.

MCVIE-MYLIE, A.J., et al, 2008 Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease. Mol Genet Metab 94: 448-455.

YOSHIMIZU, M. et al, 2008 Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human alpha-glucosidase (alglucosidase alpha): Insight into the complex formation mechanism. Clinica Chimica Acta 391: 68-73.

ZHU, Y. et al, 2005 Carbohydrate-remodelled acid a-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice. J Biochem 389: 619-628.

Information on GSD: http://medicine.med.nyu.edu/dgim/node/1041

Layman’s website on Pompe: http://www.ninds.nih.gov/disorders/pompe/pompe.htm

Good information on the genetic basis of the disease: http://www.ncbi.nlm.nih.gov/gene/2548

The Crowley family – illustration of the phenotypic defects associated with Pompe’s: http://www.crowleyfamily5.com/meet_the_crowleys.htm

Review of Pompe’s disease mechanism and treatments: http://pharmweb.usc.edu/phar406/mini_case_study/pompe.pdf

Method to treat the disease in infants: http://www.neurology.org/content/68/2/99.shortAlglucosidase alpha: http://www.dru gbank.ca/drugs/DB01272Information of

Lumizyme: http://www.in-pharmatechnologist.com/Ingredients/Myozyme-becomes-Lumizyme-after-biologics-scale-up YOSHIMIZU, M. et al, 2008 Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human alpha-glucosidase (alglucosidase alpha): Insight into the complex formation mechanism. Clinica Chimica Acta 391: 68-73.
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