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

1. Enzyme Replacement Therapy for
Lysosomal Storage Diseases
PHS Lecture Series
Roy Maynard, MD
March 18, 2010

2. Objectives
1. Understand the pathophysiology of
lysosomal storage diseases
2. Identify lysosomal storage diseases
amenable to enzyme replacement therapy
3. Understand the limitations of enzyme
replacement therapy
4. 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 Biology
Desnick 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 Recessive
http://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 Survival
http://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 weakness
http://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 infant
http://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 Disease
http://www.mda.org/publications/quest/q161RescuedLives.html. Accessed on March 15, 2010.
16

17. Electron Micrograph of Pompe
Affected Muscle Cell
http://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 Tags
http://www.mda.org/publications/quest/q76resup.html. Accessed on March 15, 2010.
21

22. Cellular Biology
http://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 antibodies
Nicolino 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 Disease
http://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 Syndrome
http://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 Syndrome
http://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 Syndrome
http://www.maroteaux-lamy.com/English/images/HCP/Patients.jpg. Accessed on March 15, 2010.
51

52. Maroteaux-Lamy Syndrome
Normal Storage Disorder
Left: In a healthy cell
with sufficient ASB
activity, lysosomes
constitute a negligible
portion of cellular
volume (about 1%).15
Right: In an MPS cell,
lysosomes, replete with
excess GAG, increase in
both size and number,
crowding the nucleus and
other 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.
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