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Enzyme Replacement Therapy for Lysosomal Storage Diseases
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?
โข Spherical organelles, discovered 1949
โข Contain enzymes (acid hydrolases)
โข Role in digestion โsuicide sacsโ
โข Low pH
โข Cellsโ garbage disposal system
3
7. Pompeโs Disease
โข Genetics
โ Autosomal recessive
โ Pan-ethnic 1/40,000 โ 1/146,000
โ Infantile and late onset forms
โ Glycogen storage disease type II
โ Acid alpha-glucosidase deficiency
โ Over 200 different mutations account for
clinical heterogeneity
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8. Pompeโs Disease
Autosomal Recessive
http://www.pompe.com/en/healthcare-professionals/genetics-epidemiology.aspx. Accessed on March 16, 2010.
8
9. Pompeโs Disease
โข Clinical features infantile form
โ Normal birth history
โ Age at presentation 2โ4 months
โ Muscle weakness, hypotonia
โ Macroglossia
โ Hypertrophic cardiomyopathy
โ Respiratory failure
โ Early death
9
10. Infantile Pompeโs Disease Survival
http://scienceroll.com/2007/02/06/pompe-disease-a-rare-but-important-genetic-condition. Accessed on March 16, 2010.
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11. Pompeโs 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. Pompeโs 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. Pompeโs Disease
โข Clinical features late onset form
โ Normal birth history
โ Heterogeneous (childhood, juvenile, adult)
โ Adult onset 2nd to 6th decade
โ Typically no severe cardiomyopathy
โ Progressive skeletal myopathy
13
15. Pompeโs Disease
โข Pathophysiology
โ Accumulation glycogen in liver, heart, skeletal
muscle, smooth muscle in GI tract, ear
โ Large glycogen deposits in muscle cells
(cardiac, skeletal, smooth) impair muscle fiber
contraction
โ 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.
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19. Pompeโs Disease
โข Enzyme replacement therapy
โ Alpha-glucosidase (GAA)
โ 1960โs enzyme replacement attempted
โ 2006 recombinant GAA available
โ IV dosing every 2 weeks
โ Early treatment โ better outcome
โ Cell-surface receptors (mannose) plays a role in
endocytosis
โข 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.
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21. Pompeโs Disease
with Mannose 6-phosphate Tags
http://www.mda.org/publications/quest/q76resup.html. Accessed on March 15, 2010.
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23. Pompeโs Disease
โข Outcome after ERT
โ Decrease glycogen in tissues
โ Improved quality and quantity of life
โ Decreased ventilator days
โ Study n=18, enrolled <7 mths/age
โข 3 needed vent within 12 mths, 4 more needed vent beyond 12
mths treatment and 2/4 died
โข 2/9 that had increased motor gains lost ground
โ 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. Pompeโs Disease Outcomes
โข French study
โ N=21, 3โ43 months age (median 13 mths)
โ Treated median 120 weeks
โ 71% alive study end
โ 44% of vent free patients at time of enrollment
remained vent free
โ Death reduced 79%
โ Vent risk reduced 58%
โ 86% functional independence skills (5 walking)
โ 52% infusion-associated reactions
โ 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 (Pompeโs)
โข Life-threatening anaphylaxis/cardiac arrest โ 1%
โข Allergic reaction โ 14 %
โข Infusion reaction โ 51%
โข 89% anti-IgG against GAA (higher incidence of
reactions in these patients and less efficacy
of GAA)
โข Serum sickness in IgG positive patients
โข Reactions can occur any time up to 2 hours after
infusion
25
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
โข Treatment
โ Palliative
โ Bone marrow transplant
โ Enzyme replacement therapy
โข Naglazymeยฎ
โข Approved in 2005
โข IV administration once/week
53
54. Maroteaux-Lamy Syndrome
โข Initial reactions occurred as late as week 55
โข The most frequent serious adverse events
related to Naglazymeยฎ occurring during
infusions included urticaria of the face and
neck, bronchospasm, respiratory distress,
and apnea.
โข Almost all patients develop IgG antibodies
54
55. Maroteaux-Lamy Syndrome
โข Outcome
โ Improved walking and stair climbing ability
โ Decreased joint pain
โ No change in facial features or skeletal
deformities
55
56. Treatment of Adverse Events
โข Stop infusion or slow down infusion
โข Steroids
โข Antihistamines
โข Epinephrine
โข B-agonist nebulizer
โข Antipyretics
56
57. Lysosomal Storage Diseases
Conclusions
โข Orphan disease for many, not funded
โข Enzyme replacement therapy very expensive
โข Long-term outcomes largely unknown
โข Limited results with CNS disease
โข Not curative
โข Difficult to target specific tissue (e.g. skeletal
muscle in Pompeโs Disease)
โข Tissues involved may not sufficiently remodel,
need to diagnose early for best results
57
58. Future Considerations
โข CNS penetration
โข Improved tissue-specific penetration
โข Stem cell transplant
โข Endogenous enzyme modulation
โข Gene therapy
โข In the future, more genetic diseases
amendable to enzyme replacement therapy
will be discovered.
58
59. Essentials of Successful Home
Treatment Program
โข Careful patient selection
โข Experienced home infusion team
โข Detailed management plan for potential
anaphylaxis and infusion-associated
reactions
59
60. Journal References
โข Burton BK, Wiesman C, Paras A, Kim K, Katz R. Mol Genet
Metab. 2009 Jul;97(3):234-6. Epub 2009 Apr 21.
โข Desnick RJ, Schuchman EH. Nat Rev Genet. 2002
Dec;3(12):954-66. Erratum in Nat Rev Genet. 2003 Feb;4(2):157.
โข Kishnani PS, Corzo D, Leslie ND, et al. Pediatr Res. 2009
Sep;66(3):329-35.
โข Nicolino M, Byrne B, Wraith JE, et al. Genet Med. 2009
Mar;11(3):210-9.
โข Roscoe O Brady. Annual Review of Medicine. 2006;57: 283-96.
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61. Suggested Reading
โข 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.
โข 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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