1. Advances in Gaucher Disease:
The Past, Present and Future
Priya S. Kishnani,
Division Chief,
Medical Genetics,
Duke University Medical Center
Metabolic Liver Disease Meeting
Mumbai, Jan 13-14, 2012
*

3. The Metabolic Defect In Gaucher Disease
Diagnostic Test : Measurement of leucocyte glucocerebrosidase
activity

5. The Gaucher Cell

7. Comparative Frequencies of
Inherited Diseases
LSDs* 1/7,700
Gaucher - AJ 1/850
Gaucher - Non-Jewish 1/40,000
Cystic fibrosis 1/2,500
PKU 1/14,000
(hypothyroidism) 1/3,500
*Meikel et al, JAMA, 1999,281,249

9. Clinical
Type 1 Gaucher Heterogeneity
Asymptomatic Mildly affected Severely affected
80-year-old man young adult girl

10. Acute Neuronopathic Gaucher Disease (Type 2)
• Strabismus
• Retroflexion of the
neck
• Cortical thumbs
• Visceromegaly
• Failure to thrive
• Cachexia

11. Type II-Neuropathology
• Glucocerebroside accumulates in brain
• Brainstem accumulation common
• Brainstem nuclei affected

13. Neuropathology in Gaucher Disease
European, US and Israeli type of Gaucher
disease
majority Type 1, rarely type 2 or type 3
Other area’s in the world such as Asia, Africa
have more neurologic Gaucher Disease
neuroprotective N370S mutation not observed
or rare

15. Natural History
Organ Tissue
Enzyme Lipid
Infiltration Damage
Deficiency Storage
With Storage Inflammation
Cells Infarction
Asymptomatic Symptomatic Fibrosis
Organomegaly Organomegaly
Splenectomy
Morbidity
Premature death

16. Cause Of Death In Type 1 Gaucher
Disease In Pre-ERT Era
• Bleeding
• Liver failure
• Infection
• Crippling bone disease
• Pulmonary hypertension
• Pulmonary failure
• Cancers
Risk markedly increased after splenectomy
RE Lee, Prog Clin Biol Res, 1981, 95, 177-215

18. Gaucher Disease – a Continuum of Phenotypes

19. Other Phenotypes
• Hydrops fetalis may be rarely seen

20. Cancer & Gaucher Disease
• Lymphoproliferative disorders more
common in Gaucher patients
– chronic lymphocytic leukemia
– multiple myeloma
– non-Hodgkin lymphoma
• Bone tumors
• Multiple myloma

21. Gaucher Genotypes

23. Genotype/Phenotype
Correlations
Genotype Phenotype
N370S/other Type 1
Gaucher allele
Type 2/3
L444P/L444P

24. Assessments
• Skeletal
– X-rays of femora, spine, symptomatic sites
– MRI of the femora
– Dual energy X-ray absorptiometry (DEXA)
• Hematological
– Hemoglobin, platelet count, marker enzymes
• Visceral
– Volumetric CT or MRI
• Pulmonary
– Doppler ECHO of heart, chest X-ray, ECG

25. Assessments (cont’d)
• Glucocerebrosidase assay
(Positive confirmation of enzyme deficiency)
• Mutation analysis/genotype
• Physical examination (PE)
• Laboratory tests as appropriate
(WBC, PT, PTT, AST, ALT, Ca, total protein,
vitamin B12, etc)
• SF-36® or Sickness Impact Health Survey (QoL)

26. Treatment paradigms
Precursors
Substrate X (Products)
Missing
enzyme
Toxic products
(Deficient
downstream
products)

27. Treatments For Gaucher Disease
• BMT - curative
• Ceredase – Early 1990s
• Cerezyme – The standard of care since 1994 for all severities
of Gaucher disease including life-threatening forms
• Miglustat – Approved 2003 for patients who cannot tolerate
Cerezyme due to side-effects or needle phobia
• Velaglucerase alpha- Approved 2010
• In development-
– ERT (Protalix, carrot based product)
– Small molecule therapy (Eliglustat Tartrate)
– Chaperone therapy

28. Response to Enzyme Therapy
Pretreatment Post-treatment
Age 8 Years, 8 Months Age 10 Years, 10 Months

29. Long Term Response To ERT
In 1028 Type 1 GD Patients
• Reverses anemia
• Reverses bleeding tendency
• Reverses hepato-splenomegaly
• Virtually eliminated bone crises
• Reverses marrow infiltration
• Improves bone density
• Reverses growth failure in children
• Splenectomy is no longer performed
• Improves quality of life indicators
Weinreb et al, ICGG, American J Med, 2002

30. Impact of ERT On Natural History of
Gaucher Disease
Causes of premature deaths in pre-ERT era :
• Bleeding 
• Liver failure 
• Infection 
• Crippling bone disease 
• Pulmonary hypertension ?
• Cancers – multiple myeloma ?
Problems eliminated by ERT
RE Lee, Prog Clin Biol Res, 1981, 95, 177-215

31. Platelet Response To ERT Stratified For
Severity Of Thrombocytopenia And Spleen Status
180 300
With Spleen Without Spleen
160 260
60<120 x103/mm3
140 220
Platelet Count (x10/mm)
120
180
100
140
80
60 <60 x103/mm3 100
<120 x 103/mm3
40 60
20 20
0 6 12 24 0 6 12 24
Months on Enzyme Replacement Therapy
Long term response to ERT in 1028 patients: American Journal of Medicine, 2003

32. Hemoglobin Response To Long Term ERT Stratified
For Severity Of Anemia In 1028 Patients
With Spleen Without Spleen
15 15
14 14
13 13
10-<12 10-<12
Hemoglobin (g/dL)
12 12
11 11
10 10
9 9
<10g/dl <10g/dl
8 8
7 7
0 6 12 24 0 6 12 24
Months on Enzyme Replacement Therapy
Long term response to ERT in 1028 patients: American Journal of Medicine, 2003

33. Reduction Of Spleen Volume By ERT
0
–10
–20
Mean Spleen Percent Change (MN)
–25.3
–30
–36.2
–40
–50
– 49.5
–60 –54.4 – 56.4
–57.1
–70
6 12 24 36 48 60
Months on ERT

34. Cerezyme® (imiglucerase for injection)
Indications and Usage
 Cerezyme® is indicated for long-term enzyme
replacement therapy (ERT) for pediatric and adult
patients with a confirmed diagnosis of type 1 Gaucher
disease that results in one or more of the following
conditions:
• Anemia
• Thrombocytopenia
• Bone disease
• Hepatomegaly or splenomegaly
Please see accompanying full prescribing information. For more information, visit
www.cerezyme.com or call Genzyme Medical Affairs at 1-800-745-4447.

35. COMPREHENSIVE TEAM APPROACH
Otolaryngologist Radiologist Pulmonologist
Hematologist Gastroenterologist
Pharmacist
Cardiologist Interventional Geneticist
Nephrologist
Family Practitioner Patient/ Obstetrician
Nurse Nutritionist
Family
Neurologist Genetic Counselor Ophthalmologist
Neurosurgeon Case Manager
Anesthesiologist
Phy/Occ therapist Dermatologist
Orthopedic Surgeon Internist Audiologist
Copyright 2005

36. Treatment Paradigms
SRT
ERT
Substrate inhibitor
UDP-Glucose + GAUCHER
UDP-Glucose +
Ceramide Ceramide
Glucosylceramide Glucosylceramide
Glucose + Glucose +
Ceramide Ceramide
Modified from the Genetics of Development and Disease Branch / NIDDK / NIH

37. Chaperone therapy for misfolded
proteins
• Misfolded proteins are unstable
• May not meet ER Quality Control
• May never go to Lysosome
Nucleus & ER Golgi Lysosome
Enzyme is misfolded
& unstable

38. Proposed Mechanism of Action for
Pharmacological Chaperones
Pharmacological
Chaperone
Endoplasmic Golgi Lysosome
Reticulum Apparatus
Reduced ER Retention Enhanced Trafficking Substrate Clearance
Protein-Chaperone Complex
Misfolded Protein
Substrate Accumulation

39. Gene replacement therapy- another
approach

40. Some advances in our understanding
• Gaucher disease and parkinsonism

41. Parkinson Disease
Gaucher Disease (GD) (PD)
• Deficiency of enzyme, • Loss of dopaminergic neurons
glucocerebrosidase and the presence of Lewy
accumulation of bodies, aggregates of proteins
glucosylceramides including α-synuclein
• Variable age of onset • Late onset,
common
• Recessive, single gene disorder • Complex multi-gene disorder
• Multi-organ involvement • Mainly affects substantia nigra
and brainstem
• Symptoms include enlarged • Symptoms include bradykinesia,
spleens and livers, low platelet rigidity and tremor, and
counts, bone and brain frequently, dementia
involvement

42. GBA mutations are associated with parkinsonism
• Rare group of patients have both Gaucher disease (GD) and
parkinsonism
• Relatives of Gaucher probands have increased frequency of
parkinsonism
• 12% of brain bank samples with pathologically confirmed PD
had GBA mutations (Gaucher carrier frequency 0.6% in general population and
3.4% in Ashkenazi Jewish)
• PD cohorts of different ethnicities have an increased frequency of
GBA mutations
• Patients with other synucleinopathies also have GBA mutations

43. Gaucher
Disease
? Parkinsonism
• How are these two disorders related?

44. Brain samples show Lewy bodies, inclusions
characteristic of Parkinson disease and
related disorders.
H&E, 400X -Synuclein antibody,
200X

45. ERT for Gaucher Disease in India
• Retrospective analysis of Gaucher patients receiving CHO-
derived recombinant macrophage-targeted
glucocerebrosidase ; Performed through 5 centers in India
• 25 of 52 patients diagnosed with Gaucher (17 Type I and 8
mild Type III) received treatment >6 months; Infusions given
every 15 days
• Indications for treatment included symptomatic anemia,
thrombocytopenia, organomegaly, bone disease, or mild
neurological impairment leading to impairment of quality of
life.
• 22 of the 25 children who survived were analyzed
Nagral A, Mewawalla P, Jagadeesh S, Kabra M, Phadke SR, Verma IC, Puri RD, Gupta N, Kishnani PS, Mistry PK.
Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr.
2011 Oct;48(10):779-84.

46. ERT for Gaucher Disease in India
After 6 months:
• Mean increase in hemoglobin 1.5 g/dL; Mean increase in platelets 32 x 10˄9/L
• Mean increase in weight 3 kg; Mean increase in height 7.1 cm
• Liver size decreased by mean range of 38.5% and spleen size decreased by mean
range of 34.8%
• All patient had improvement in bone pain
• In 2 patients, neurological symptoms improved; Remained static in all others
Nagral A, Mewawalla P, Jagadeesh S, Kabra M, Phadke SR, Verma IC, Puri RD, Gupta N, Kishnani PS, Mistry PK. Recombinant
macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr. 2011 Oct;48(10):779-84.

47. Acknowledgements
• Colleagues at Duke University
• Colleagues in India
• Colleagues from ICGG
• Pramod Mistry, MD
• Most importantly our patients who teach
us everyday