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CURRENT AND FUTURE STRATEGIES FOR THE TREATMENT OF METABOLIC STORAGE DISORDERS

CURRENT AND FUTURE STRATEGIES FOR THE TREATMENT OF METABOLIC STORAGE DISORDERS 1. BONE MARROW TRANSPLANTATION 2. ENZYME REPLACEMENT THERAPY 3. SUBSTRATE REDUCTION THERAPY 4. MOLECULAR CHAPERONE THERAPY 5. GENE THERAPY.

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CURRENT AND FUTURE STRATEGIES FOR THE TREATMENT OF METABOLIC STORAGE DISORDERS

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  1. CURRENT AND FUTURE STRATEGIES FOR THE • TREATMENT OF METABOLIC STORAGE DISORDERS • 1. BONE MARROW TRANSPLANTATION • 2. ENZYME REPLACEMENT THERAPY • 3. SUBSTRATE REDUCTION THERAPY • 4. MOLECULAR CHAPERONE THERAPY • 5. GENE THERAPY

  2. Hereditary Lipid Storage Disorders Sphingolipidoses

  3. SPHINGOSINE CH3 -(CH2)12-CH=CH-CH-CH-CH2OH OH NH2 3 2 1 18 Carbon atoms 1 and 2 arise from the amino acid serine Carbon atoms 3 to 18 arise from palmitic acid

  4. CERAMIDE Sphingosine CH3 -(CH2)12-CH=CH-CH-CH-CH2OH OH NH CH3 - (CH2)22 - C = 0 Long Chain Fatty Acid

  5. GAUCHER DISEASE

  6. Gaucher Disease Type 1 (Non- Neuronopathic) Anemia Easy bruising due to low blood platelets Bone damage Enlarged liver Huge spleen

  7. ACCUMULATING LIPID IN GAUCHER DISEASE GLUCOCEREBROSIDE SPHINGOSINE GLUCOSE FATTYACID

  8. ENZYMATIC DEFECT IN GAUCHER DISEASE DEFICIENCY OF GLUCOCEREBROSIDASE SPHINGOSINE GLUCOSE FATTY ACID R. O. Brady et al. Biochem Biophys Res Commun 1965; 18: 221

  9. WHAT IS THE ORIGIN OF THE ACCUMULATING LIPID?

  10. MAJOR LIPID OF WHITE BLOOD CELLS CERAMIDELACTOSIDE SPHINGOSINE GLUCOSE GALACTOSE FATTY ACID

  11. MAJOR LIPID OF RED BLOOD CELLS GLOBOSIDE SPHINGOSINE—GLUCOSE—GALACTOSE—GALACTOSE—N-ACETYGALACTOSAMINE FATTY ACID • 20-40 times more glucocerebroside arises from senescent • white blood cells than red blood cells

  12. TREATMENT OF PATIENTS WITH LYSOSOMAL STORAGE DISORDERS Bone Marrow Transplantation

  13. BONE MARROW TRANSPLANTATION (BMT) If a suitable match is available, BMT can cure a patient with type 1 Gaucher disease Risks Graft-versus host disease Continuous immunosuppression probably necessary Implication ? Gene therapy using transduced bone marrow stem cells

  14. TREATMENT STRATEGIES 2. ENZYME REPLACEMENT THERAPY R. O. BRADY N Engl J Med 1966; 275: 312

  15. GAUCHER DISEASE The required enzyme glucocerebrosidase is currently produced recombinantly in Chinese hamster ovary cells. It is necessary to modify the glycoform of this enzyme in order to target it to macrophages, the principal lipid- storing cells in the body of patients.

  16. Amino Acid Chain

  17. GLUCOCEREBROSIDASE IS TREATED WITH 3 EXOGLYCOSIDASES

  18. Amino Acid Chain

  19. Delivery of mannose-terminal glucocerebrosidase to lipid-storing macrophages (Kupffer cells in the liver) is increased 50-fold over that of unmodified glucocerebrosidase

  20. RESULTS OF ENZYME REPLACEMENT THERAPY IN GAUCHER PATIENTSUSING MACROPHAGE- TARGETED GLUCOCEREBROSIDASE Spleen size decreases Liver size decreases Hemoglobin increases Blood platelets increase Skeleton improves

  21. SPLEEN MRI OF ABDOMEN ERT 7 months ERT

  22. MORE THAN 4,300 PATIENTS WITH GAUCHER DISEASE ARE NOW RECEIVING ENZYME REPLACEMENT THERAPY

  23. TYPE 2 GAUCHER DISEASE Acute Neuronopathic Gaucher Disease

  24. Neuronophagia in the brain of a patient with Type 2 Gaucher disease

  25. WHAT IS THE SOURCE OF GLUCOCEREBROSIDE IN THE BRAIN?

  26. Ganglioside GDIa SPHINGOSINE -GLUCOSE -GALACTOSE- N-ACETYGALACTOSAMINE- GALACTOSE FATTY ACID N-ACETYLNEURAMINIC ACID N-ACETYLNEURAMINIC ACID

  27. ENZYME REPLACEMENT THERAPY IN PATIENTS WITH TYPE 2 GAUCHER DISEASE No benefit of intravenous glucocerebrosidase on brain

  28. WOULD DIRECTINTRACEREBRAL INJECTION OF GLUCOCEREBROSIDASE BE EFFECTIVE? (CONVECTION-ENHANCED DELIVERY)

  29. Safety and Distribution of Mannose-terminal Glucocerebrosidase Injected into the Brain of Normal Rats G.C. Zirzow et al. Neurochemical Res 1999; 24: 301

  30. NEURONAL UPTAKE OF INTRA-CEREBRALLY ADMINISTERED GLUCOCEREBROSIDASE

  31. Safety Study of Intracerebrally Injected Glucocerebrosidase in Non-human Primates R. Lonser et al, Annals of Neurology 2005; 57: 543

  32. TREATMENT STRATEGIES 3. SUBSTRATE REDUCTION THERAPY

  33. REDUCE THE FORMATION OF GLUCOCEREBROSIDE SPHINGOSINE + UDP–GLUCOSE SPHINGOSINE GLUCOSE + UDP FATTY ACID FATTY ACID Glucocerebroside UDP-GLUCOSE = URIDINE DIPHOSPHATE GLUCOSE = SITE OF INHIBITION OF GLUCOSYLTRANSFERASE

  34. Small Molecule Inhibitor of Glucocerebroside Formation MIGLUSTAT

  35. SUBSTRATE DEPLETION MiglustatOGT 918 (Zavesca) has been approved for the treatment of patients with type 1 Gaucher disease for whom enzyme replacement therapy is not appropriate. (Cox T, Lachmann R, Hollak C, et al. Lancet 2000; 355: 1481)

  36. Patient with Type 3a Chronic Neuronopathic Gaucher Disease Slow horizontal eye movement

  37. SUBSTRATE DEPLETION • Ongoing NIH Investigation of OGT 918 in • Patients with Type 3 (Chronic Neuronopathic) • Gaucher Disease Who Also Receive Enzyme • Replacement Therapy to Control the Systemic • Manifestations of the Disease

  38. TREATMENT STRATEGIES 4. MOLECULAR CHAPERONE THERAPY

  39. GM1-GANGLIOSIDOSIS

  40. GM1 Gangliosidosis Phenotypes Infantile Juvenile Chronic Adult Adult

  41. Accumulation of Ganglioside GM1 SPHINGOSINE-GLUCOSE-GALACTOSE-N-ACETYGALACTOSAMINE-GALACTOSE FATTY ACID N-ACETYLNEURAMINIC ACID

  42. Enzymatic Defect in GM1-Gangliosidosis SPHINGOSINE-GLUCOSE-GALACTOSE-N-ACETYGALACTOSAMINE-GALACTOSE FATTY ACID N-ACETYLNEURAMINIC ACID -galactosidase deficiency Okada and O’Brien 1968

  43. CHEMICAL CHAPERONE THERAPY FOR BRAIN PATHOLOGY IN GM1-GANGLIOSIDOSIS

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