1. Advances in Gaucher Disease:
The Past, Present and Future
Priya S. Kishnani,
Division Chief,
Medical Genetics,
Duke University Medical Center
MID-TERM SINGLE THEME CONFERENCE METABOLIC LIVER DISEASE
JAN 2012
2.
3. The Metabolic Defect In Gaucher Disease
Diagnostic Test : Measurement of leucocyte glucocerebrosidase activity
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
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
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
Pre-treatment
Age 8 Years, 8 Months
Post-treatment
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
300
180
Without Spleen
With Spleen
Platelet Count (x10/mm)
160
260
60<120 x103/mm3
140
220
120
180
100
140
80
<60 x103/mm3
60
100
<120 x 103/mm3
60
40
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
Without Spleen
With Spleen
15
14
14
13
Hemoglobin (g/dL)
15
13
10-<12
12
11
11
10
10
9
10-<12
12
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
Mean Spleen Percent Change (MN)
–10
–20
–30
–25.3
–36.2
–40
–50
– 49.5
–60
–54.4
–57.1
– 56.4
–70
6
12
24
36
Months on ERT
48
60
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.
36. Treatment Paradigms
SRT
Substrate inhibitor
UDP-Glucose +
Ceramide
ERT
GAUCHER
UDP-Glucose +
Ceramide
Glucosylceramide
Glucosylceramide
Glucose +
Ceramide
Glucose +
Ceramide
Modified from the Genetics of Development and Disease Branch / NIDDK / NIH
37. Chaperone therapy for mis-folded
proteins
• Mis-folded proteins are unstable
• May not meet ER Quality Control
• May never go to Lysosome
Golgi
Nucleus & ER
Enzyme is mis-folded
& unstable
Lysosome
38. Proposed Mechanism of Action for
Pharmacological Chaperones
Pharmacological
Chaperone
Endoplasmic
Reticulum
Golgi
Apparatus
Lysosome
Reduced ER Retention
Enhanced Trafficking
Substrate Clearance
Protein-Chaperone Complex
Misfolded Protein
Substrate Accumulation
40. Some advances in our understanding
• Gaucher disease and parkinsonism
41. Gaucher Disease (GD)
Parkinson Disease
(PD)
• Deficiency of enzyme,
glucocerebrosidase
accumulation of
glucosylceramides
• Loss of dopaminergic neurons
and the presence of Lewy
bodies, aggregates of proteins
including α-synuclein
• Variable age of onset
• Late onset,
common
• Complex multi-gene disorder
• Recessive, single gene disorder
• Multi-organ involvement
• Mainly affects substantia nigra
and brainstem
• Symptoms include enlarged
spleens and livers, low platelet
counts, bone and brain
involvement
• Symptoms include bradykinesia,
rigidity and tremor, and
frequently, dementia
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
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 CHOderived 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.
