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Enzyme Replacement Therapy for Lysosomal Storage Diseases

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Dr. Maynard's lecture on novel new therapies for treating Lysosomal Storage diseases (presented on 3/18/10).

Dr. Maynard's lecture on novel new therapies for treating Lysosomal Storage diseases (presented on 3/18/10).

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  • 1. Enzyme Replacement Therapy for Lysosomal Storage Diseases PHS Lecture Series Roy Maynard, MD March 18, 2010
  • 2. Objectives1. Understand the pathophysiology of lysosomal storage diseases2. Identify lysosomal storage diseases amenable to enzyme replacement therapy3. Understand the limitations of enzyme replacement therapy4. Recognize side effects of IV enzyme replacement therapy 2
  • 3. What is a Lysosome?• Spherical organelles, discovered 1949• Contain enzymes (acid hydrolases)• Role in digestion “suicide sacs”• Low pH• Cells’ garbage disposal system 3
  • 4. Lysosomal Functions• Phagocytosis• Endocytosis• Exocytosis• Autophagy• Foreign microbe destruction 4
  • 5. Cellular BiologyDesnick RJ, Schuchman EH. Nat Rev Genet. 2002 Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157. 5
  • 6. Lysosomal Storage Diseases• Mucopolysaccharidoses• GM2 gangliosidoses• Lipid storage disorders• Glycoproteinoses• Mucolipidoses• Leukodystrophies 6
  • 7. Pompe’s Disease• Genetics – Autosomal recessive – Pan-ethnic 1/40,000 – 1/146,000 – Infantile and late onset forms – Glycogen storage disease type II – Acid alpha-glucosidase deficiency – Over 200 different mutations account for clinical heterogeneity 7
  • 8. Pompe’s Disease Autosomal Recessivehttp://www.pompe.com/en/healthcare-professionals/genetics-epidemiology.aspx. Accessed on March 16, 2010. 8
  • 9. Pompe’s Disease• Clinical features infantile form – Normal birth history – Age at presentation 2–4 months – Muscle weakness, hypotonia – Macroglossia – Hypertrophic cardiomyopathy – Respiratory failure – Early death 9
  • 10. Infantile Pompe’s Disease Survivalhttp://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition. Accessed on March 16, 2010. 10
  • 11. Pompe’s Disease Head lag caused by muscle weaknesshttp://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010. 11
  • 12. Pompe’s Disease Cardiomegaly in infanthttp://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition/. Accessed on March 15, 2010. 12
  • 13. Pompe’s Disease• Clinical features late onset form – Normal birth history – Heterogeneous (childhood, juvenile, adult) – Adult onset 2nd to 6th decade – Typically no severe cardiomyopathy – Progressive skeletal myopathy 13
  • 14. Pompe’s Disease• Diagnosis – Low or absent acid alpha glucosidase (GAA) – Muscle, fibroblast biopsy (gold standard) – Histopath vacuoles PAS stain positive – EKG (conduction, arrythmias) – Elevated creatinine kinase – DNA mutation analysis – Elevated liver enzymes 14
  • 15. Pompe’s Disease• Pathophysiology – Accumulation glycogen in liver, heart, skeletal muscle, smooth muscle in GI tract, ear – Large glycogen deposits in muscle cells (cardiac, skeletal, smooth) impair muscle fiber contraction – Ultimately there is gross muscle hypertrophy due to increased glycogen storage at the expense of muscle atrophy and destruction 15
  • 16. Glycogen Buildup in Pompe Diseasehttp://www.mda.org/publications/quest/q161RescuedLives.html. Accessed on March 15, 2010. 16
  • 17. Electron Micrograph of Pompe Affected Muscle Cellhttp://www.pompe.com/en/healthcare-professionals/overview/pathology.aspx. Accessed on March 15, 2010. 17
  • 18. Pompe’s Disease• Treatment – Supportive • Respiratory • Nutritional • Musculoskeletal/rehab • Cardiac 18
  • 19. Pompe’s Disease• Enzyme replacement therapy – Alpha-glucosidase (GAA) – 1960’s enzyme replacement attempted – 2006 recombinant GAA available – IV dosing every 2 weeks – Early treatment – better outcome – Cell-surface receptors (mannose) plays a role in endocytosis• Mannose-6-phosphate (M6P) tag on enzymes 19
  • 20. Myozyme Production Production of acid a-glucosidase in Chinese hamster ovary (CHO-) cells and in the milk of transgenic rabbits.http://www.pompecenter.nl/en/?History. Accessed on March 16, 2010. 20
  • 21. Pompe’s Disease with Mannose 6-phosphate Tagshttp://www.mda.org/publications/quest/q76resup.html. Accessed on March 15, 2010. 21
  • 22. Cellular Biologyhttp://www.mda.org/publications/quest/q102pompe.html. Accessed on March 15, 2010. 22
  • 23. Pompe’s Disease• Outcome after ERT – Decrease glycogen in tissues – Improved quality and quantity of life – Decreased ventilator days – Study n=18, enrolled <7 mths/age • 3 needed vent within 12 mths, 4 more needed vent beyond 12 mths treatment and 2/4 died • 2/9 that had increased motor gains lost ground – Decrease in LV size (no correlation to clinical outcome)Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009 Sep;66(3):329-35. 23
  • 24. Pompe’s Disease Outcomes• French study – N=21, 3–43 months age (median 13 mths) – Treated median 120 weeks – 71% alive study end – 44% of vent free patients at time of enrollment remained vent free – Death reduced 79% – Vent risk reduced 58% – 86% functional independence skills (5 walking) – 52% infusion-associated reactions – 95% IgG antibodiesNicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009 Mar;11(3):210-9. 24
  • 25. Complications of Enzyme Replacement Therapy (Pompe’s)• Life-threatening anaphylaxis/cardiac arrest – 1%• Allergic reaction – 14 %• Infusion reaction – 51%• 89% anti-IgG against GAA (higher incidence of reactions in these patients and less efficacy of GAA)• Serum sickness in IgG positive patients• Reactions can occur any time up to 2 hours after infusion 25
  • 26. Complications of Enzyme Replacement Therapy (Pompe’s)• 100% of patients had adverse events – Fever – Decrease oxygen sats – Tachycardia – Cyanosis – Hypotension – Rash, urticaria, flushing, pallor – Bronchospasm 26
  • 27. Gaucher’s Disease• Sometimes called glucocererebrosidase deficiency• Most prevalent metabolic storage disorder• Lipid storage disorder• Accumulation of glucosylceramide• Spleen, bone, and liver• Enzyme replacement since 1994• Genetics autosomal recessive• 1/50,000 births, European Jewish population 27
  • 28. Gaucher’s Disease• Clinical signs and symptoms – Easy bruising and bleeding – Fatigue – Anemia – Weak bones and fractures – Bone and joint pain – Hepatospleenomegaly 28
  • 29. Gaucher’s Disease• Diagnosis – DNA mutation analysis chromosome 1 – Enzyme levels in blood or fibroblasts – Deficient glucocerebrosidase 29
  • 30. Gaucher’s Disease 30
  • 31. Gaucher’s Diseasehttp://wikidoc.org/images/thumb/e/e9/Gaucher_disease_004.jpg/400px-Gaucher_disease_004.jpg.Accessed on March 16, 2010. 31
  • 32. Gaucher’s Disease• Enzyme replacement therapy – Cerezyme – Administered IV usually q 2 weeks – Allergic reactions – Reduction in symptoms – 13.8% adverse events – 1% < anaphylaxis 32
  • 33. Fabry’s Disease• Alpha galactosidase A deficiency• Accumulates glycolipid – globotriaosylceramide (GL-3)• Blood vessels (vascular endothelium)• Genetics – X-linked recessive – Males>females – 1/40,000–60,000 males – Survival mean age 41 33
  • 34. Fabry’s Disease and Hunter Syndrome X-linked Recessive 34
  • 35. Fabry’s Disease• Clinical signs and symptoms – Renal failure 3rd decade – Cardiac – cardiomyopathy, hypertension – Skin – angiokeratomas, anhidrosis – Eyes – corneal issues – Neurostroke, fatigue, neuropathy – Pain in extremities 35
  • 36. Fabry’s Disease• Diagnosis – Blood enzyme levels alpha-galactosidase – Chomosomal analysis of GLA gene for DNA mutation 36
  • 37. Fabry’s Disease• Treatment – Enzyme replacement therapy – Fabrazyme® (Genzyme Corp.) – Replagal® (Shire) 37
  • 38. Fabry’s Disease Outcome• Decreased GL3 in tissues• May ameliorate disease expression 38
  • 39. Hurler’s Syndrome• Mucopolysaccharidoses I (MPS I) – Autosomal recessive (chromosome 4) 1/100,000 births – Alpha-L-Iduronidase (Aldurazyme®) • Aldurazyme® is manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corp. – Accumulate dermatan and heparin sulphate 39
  • 40. Hurler’s Syndrome• Clinical features – Progressive deterioration – Large liver and spleen – Dwarfism – Hearing loss – Macroglossia – Mental retardation – Cloudy corneas – Limited joint movement – Respiratory abnormalities 40
  • 41. Hurler’s Syndromehttp://deti.msk.ru/plaxin_egor.jpg. Accessed on March 15, 2010. 41
  • 42. Hurler’s Syndrome• Variations amenable to enzyme replacement therapy include Hurler-Scheie and Scheie Syndrome• Aldurazyme® 42
  • 43. Hurler’s Syndrome• Outcome – Increased walk distance – Increased FVC – Decreased liver and spleen size 43
  • 44. Hurler’s Syndrome• Adverse events – 97% positive for IgG antibody – Anaphylaxis – 35% infusion-related reactions • Fever • Chills • Hypotension • Tachycardia • Decreased oxygen sats 44
  • 45. Hunter Syndrome• Mucopolysaccharidosis II – Deficiency iduronate-2-sulfatase (Elaprase® - Shire) – Dermatan and heparin sulfate – X-linked recessive (rare disease, >200 mutations) – Airway obstruction – Skeletal deformities – Cardiomyopathy – Neurological decline – Death 2nd decade 45
  • 46. Hunter Syndromehttp://davechidley.ca/wp-content/uploads/2009/02/szymon-cajmer900w.jpg. Accessed on March 15, 2010. 46
  • 47. Complications of Elaprase® Therapy for Hunter Syndrome• Anaphylaxis (biphasic anaphylaxis 24 hrs after infusion)• Respiratory distress, hypoxia, seizure, hypotension• Fever – 63%• Headache – 59%• Joint pain – 31%• 51% have IgG against Elaprase® 47
  • 48. Hunter Syndrome• Outcome – Increased walking capacity – Trend towards increased FVC – Decreased organ size 48
  • 49. Maroteaux-Lamy Syndrome• Mucopolysaccharidosis VI (MPS VI) – Arylsulphatase B deficiency (Naglazyme® – BioMarin Pharmaceutical Inc.) – Accumulate dermatan sulphate – Genetics • Autosomal recessive • Rare disorder 49
  • 50. Maroteaux-Lamy Syndrome• Clinical signs and symptoms – Coarse facial features – Skeletal damage – Hepatospleenomegaly – Corneal clouding – Cardiac valvular disease – Short stature – Normal intelligence – Respiratory 50
  • 51. Maroteaux-Lamy Syndromehttp://www.maroteaux-lamy.com/English/images/HCP/Patients.jpg. Accessed on March 15, 2010. 51
  • 52. Maroteaux-Lamy Syndrome Normal Storage DisorderLeft: In a healthy cellwith sufficient ASBactivity, lysosomesconstitute a negligibleportion of cellularvolume (about 1%).15Right: In an MPS cell,lysosomes, replete withexcess GAG, increase inboth size and number,crowding the nucleus andother critical organelles,engorging the cell.http://www.naglazyme.com/en/Images/Patients/StorageDisorderCells.JPG. Accessed on March 15, 2010. 52
  • 53. Maroteaux-Lamy Syndrome• Treatment – Palliative – Bone marrow transplant – Enzyme replacement therapy • Naglazyme® • Approved in 2005 • IV administration once/week 53
  • 54. Maroteaux-Lamy Syndrome• Initial reactions occurred as late as week 55• The most frequent serious adverse events related to Naglazyme® occurring during infusions included urticaria of the face and neck, bronchospasm, respiratory distress, and apnea.• Almost all patients develop IgG antibodies 54
  • 55. Maroteaux-Lamy Syndrome• Outcome – Improved walking and stair climbing ability – Decreased joint pain – No change in facial features or skeletal deformities 55
  • 56. Treatment of Adverse Events• Stop infusion or slow down infusion• Steroids• Antihistamines• Epinephrine• B-agonist nebulizer• Antipyretics 56
  • 57. Lysosomal Storage Diseases Conclusions• Orphan disease for many, not funded• Enzyme replacement therapy very expensive• Long-term outcomes largely unknown• Limited results with CNS disease• Not curative• Difficult to target specific tissue (e.g. skeletal muscle in Pompe’s Disease)• Tissues involved may not sufficiently remodel, need to diagnose early for best results 57
  • 58. Future Considerations• CNS penetration• Improved tissue-specific penetration• Stem cell transplant• Endogenous enzyme modulation• Gene therapy• In the future, more genetic diseases amendable to enzyme replacement therapy will be discovered. 58
  • 59. Essentials of Successful Home Treatment Program• Careful patient selection• Experienced home infusion team• Detailed management plan for potential anaphylaxis and infusion-associated reactions 59
  • 60. Journal References• Burton BK, Wiesman C, Paras A, Kim K, Katz R. Mol Genet Metab. 2009 Jul;97(3):234-6. Epub 2009 Apr 21.• Desnick RJ, Schuchman EH. Nat Rev Genet. 2002 Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157.• Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009 Sep;66(3):329-35.• Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009 Mar;11(3):210-9.• Roscoe O Brady. Annual Review of Medicine. 2006;57: 283-96. 60 60
  • 61. Suggested Reading• Kishnani PS, Steiner RD, Bali D, Berger K, et al: Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. No abstract available. Erratum in: Genet Med. 2006 Jun;8(6):382.• Muenzer J, Wraith JE, Clarke LA: Mucopolysaccharidosis I: management and treatment guidelines. International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Pediatrics. 2009 Jan;123(1):19-29. 61

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