1. Gaucher Disease: Overview and goals for current therapy
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Gaucher Disease: Overview and goals for current therapy
Ozlem Goker-Alpan, MD
Lysosomal Storage Disorders Research and Treatment Unit, CFCT
Fairfax, VA
Gaucher Disease: Overview and Therapeutic Goals

2. Gaucher Disease: A Lysosomal Storage Disorder
Most common lysosomal storage disorder
Autosomal recessive
Genetic defect on chromosome 1
Enzyme deficiency
Reticuloendothelial system
Progressive, multisystemic, multiorgan dysfunction
Gaucher Disease: A Lysosomal Storage Disorder
Gaucher’s Disease–rare inherited disease; deficiency or lack of an enzyme called Glucocereborsidase
Results in an accumulation of glucocerebroside within cells in various body tissues (spleen, liver, bone marrow, and skeleton)
Severity of the disease can vary
References
Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41 (suppl 5):4-14.
Ginns EI, Choudary PV, Tsugi S, et al. Gene mapping and leader polypeptide sequence of human glucocerebrosidase: Implications for Gaucher disease. Proc Natl Acad Sci USA. 1985;82:
Philippe Gaucher 1854 – 1918
1. Pastores GM, et al. Semin Hematol. 2004;41 (suppl 5): 4– Ginns EI, et al. Proc Natl Acad Sci USA. 1985;82:7101–7105. 2

3. Normal cell Lysosome Cell Nucleus Enzyme Glucosylceramide
Here is how the cell’s lysosomes are disrupted in people with Hunter syndrome.
This drawing represents a typical cell. Within the cell you can see the nucleus as well as some lysosomes. Within the lysosomes are enzymes that assist in recycling glycosaminoglycans (GAGs)—substances that are present in cells as a result of certain metabolic processes.1,2
References: 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001: Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008;15(3):
Nucleus
Enzyme
Glucosylceramide

4. Glycosphingolipids \build up in cells throughout the body due to a deficiency or absence of the lysosomal enzyme Glucocerebrosidase. The buildup interferes with the way certain cells and organs in the body work, enlarges both cells and certain organs, and leads to symptoms, many of which are serious.
This drawing shows what happens in people with Hunter syndrome. In this case, the I2S enzyme is missing or appears in very small amounts and, as a result, the GAGs are not cleared. They continue to build up in the cell. This causes certain cells and organs to become enlarged and stop working properly, a process that leads to symptoms, many of which are serious.1,2
References: 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001: Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008;15(3):

5. Gaucher Disease: Clinical Signs and Symptoms
Pulmonary involvement
Progressive neurologic symptoms*
Hepatosplenomegaly
Skeletal involvement
Thrombocytopenia and anemia
* In neuronopathic subtypes only.
Gaucher Disease: Clinical Signs and Symptoms
Excess accumulation of glucosylceramide in macrophages leads to hepatosplenomegaly, thrombocytopenia and anemia, skeletal involvement, and less commonly, pulmonary involvement
The visceral manifestations are common to all variants of Gaucher disease, but progressive neurologic symptoms are characteristic of neuronopathic type 2 and type 3 Gaucher disease
Reference
Grabowski GA. Lysosomal storage disease 1. Phenotype, diagnosis, and treatment of Gaucher disease. Lancet. 2008;372:1263–1271.
Grabowski GA. Lancet. 2008;372:1263–1271.

6. Gene (GBA)
A309V C342G
W312C R359Q Y313H S364T T3231 E326K
84GG 1023C DEL
R120Q K157Q P122S
D140H
R463C L425E
R463Q
1VS2+1 5` 3` 1 2 3 4 5 6 7 8 9 10 11
W378G D399N
N370S D409H *
D380N D409V
D380A P415R
55 bp del* F417V
V394L
R463C
G478S
R496H
A176N Y212H
G202R P182T
N188S* F213 I
GBA
Located on chromosome 1 at 1q21
11 exons, mRNA 7604-bp
Potential promoters: 2 TATA & 2 CAT
2 ATG start sites, both equally efficient
F216Y
R257Q
R285C
289L
The Gene
Although there is not a clear genotype-phenotype correlation, some alleles are associated with distinct clinical types, ie N370S allele is associated with adult-onset (type1) GD, where as homozygosity for L444P indicates neuronopathic involvement. D409H/D409H is associated with cardiac calcifications, hydrocephalus, and N188S allele is associated with myoclonic encephalopathy .
Complex Allele A (Rec Nci) *L444P, A456P, V460V
Complex Allele B (Rec TL)
*D409H, L444P, A456P, V460V
Adapted from Hruska, KS, et al. Human Mutation. 2008;29(5):567–583.

7. The Gaucher Cell Glucocerebroside Ceramide Glucose Glucocerebrosidase
Metabolic product
(e.g., cell membrane of erythrocytes)
Glucocerebroside
Glucocerebrosidase
The Gaucher Cell
Figure: The inherited deficiency of lysosomal glucocerebrosidase leads to the abnormal accumulation of the lipid substrate glucocerebroside (glucosylceramide) in cell of RES. Lipid engorged macrophages, hallmark for Gaucher disease, are not indolent storage cells, but activate immune system
Enzyme defect causing Gaucher disease
Ceramide
Glucose
Source: Adapted from Sidranksy E. Mol Gen Metab

8. Spectrum in Gaucher Disease
Type 2
Type 3
Type 1
Neurologic manifestations
Asymptomatic
Hydrops fetalis
Skeletal disease
Congenital icthyosis
Visceral disease
2 neurologic involvement o
Progressive neurologic degeneration
Phenotypic Spectrum in Gaucher Disease
Similar to all other LSDs, GD has infantile, juvenile and adult clinical subtypes, or clinical types are based on involvement of nervous system and the progression of symptoms. Adult onset or type 1 GD is the clinical type where CNS is spared. In type 2 (acute) and type 3 (chronic) neuronopathic GD, there is a spectrum of neurological manifestations with variable rates of progression. However, some recently defined phenotypes, such as the observation of parkinsonian manifestations in both patients with GD and GD carriers defies this classical definition
Parkinsonian manifestations
Myoclonic epilepsy
Hydrocephalus, cardiac valve calcifications
Eye movement disorder
The individual clinical manifestation, rather than the subtype or genotype, may be the best guide for predicting clinical outcome
Adapted from Sidransky E. Mol Gen Metab. 2004;83:6–15. 8

9. When to Suspect Gaucher Disease and Establishing the Diagnosis
Observations
Splenomegaly in any age group
Nosebleeds and unexplained bruising
Persistent anemia or thrombocytopenia
Bone pain
Failure to thrive
Neurologic deterioration in a young infant
Congenital ichthyosis
Horizontal gaze disorder or visual apraxia
When to Suspect Gaucher Disease and Establishing the Diagnosis
After clinical suspicion has been raised, diagnosis can be confirmed by
Enzymatic analysis in white blood cell pellet in expert lab
Mutation analysis
Bone marrow biopsy is NOT required for the diagnosis
Goker-Alpan O, et al. J Med Genet. 2005;42:e37.

10. A Comprehensive Management Plan
Developed in 2003–2004 by a group of physicians from around the world with clinical expertise in treating Gaucher patients (ICGG)
Targeted areas of improvement:
Organ size
Liver volume
Spleen volume
Hematological
Pulmonary
Skeletal system
Pediatric patients
Functional health and well-being
Time frames that are described are based on past experience with alglucerase/imiglucerase
Most patients will have multiple therapeutic goals
To be completed within an expected timeframe
A Comprehensive Management Plan
A comprehensive management plan should have defined specific management goals. These goals act as a guide for managing physicians, consulting specialists, allied health personnel, educates patient and families, and establishes reasonable expectations. Most patients will have multiple therapeutic goals that should be completed within an expected timeframe and maintained for life. The success of the management goals depends on comprehensive initial assessment of all potentially affected organs and systems and regular monitoring
Reference
Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41(4Suppl 5):4–14.
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

11. Therapeutic Goals: Anemia and Thrombocytopenia*
Anemia Patients
Goal
Time Frame**
Adult female patients and children
Hb ≥ 11.0 g/dL
Years 1 to 2
Male patients > 12 years
Hb ≥ 12.0 g/dL
All patients
Eliminate blood transfusion
Reduce fatigue
Maintain improved Hb levels
Therapeutic Goals: Anemia and Thrombocytopenia
* Please note regular assessments will be conducted
* * Time frames that are described are based on past experience with alglucerase/imiglucerase
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

12. Therapeutic Goals: Anemia and Thrombocytopenia*
Thrombocytopenia Patients
Goal
Time Frame**
All patients
Sufficient platelets to reduce bleeding
Year 1
Splenectomized patients
Normalization of platelet counts
Intact spleen
Moderate thrombocytopenia (> 60,000–< 120,000/mm3)
Severe thrombocytopenia (< 60,000/mm3)
Approach low-normal platelet counts
Doubling by year 2 but normalization not expected
Year 2
Therapeutic Goals: Anemia and Thrombocytopenia
* Please note regular assessments will be conducted
* * Time frames that are described are based on past experience with alglucerase/imiglucerase
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

13. Therapeutic Goals: Hepatosplenomegaly
Hepatomegaly*
Patients
Goal
Time Frame**
All patients
Reduce liver volume to 1–1.5 times normal and maintain
Reduce liver volume by 20–30%
Reduce liver volume by 30–40%
Years 1 to 2
Years 3 to 5
Splenomegaly*
Patients
Goal
Time Frame**
All patients
Reduce spleen volume to ≤ 2 to 8 times normal and maintain
Reduce spleen volume by 30–50%
Reduce spleen volume by 50–60%
Year 1
Years 2 to 5
Alleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarction
Eliminate hypersplenism
Therapeutic Goals: Hepatosplenomegaly
* Please note regular assessments will be conducted
* * Time frames that are described are based on past experience with alglucerase/imiglucerase
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

14. Lessen or eliminate bone pain Prevent osteonecrosis
For bone disease, what may not be an expected outcome in patient with GD?
(D)
Lessen or eliminate bone pain
Prevent osteonecrosis
Improve Bone Mineral Density
Decrease cystic changes
Audience Response Question #4
For bone disease, what may not be an expected outcome for this patient?
Lessen or eliminate bone pain
Prevent osteonecrosis
Improve BMD
Decrease cystic changes (correct response)
Answer = D. Decrease cystic changes

15. Challenges in Counseling
Based on the carrier frequency many if not most adult patients are undiagnosed or asymptomatic
Counseling on clinical prognosis is limited because of the broad phenotypic spectrum within and between families
Challenges in Counseling

16. New(er) Enzymes for the treatment of
Gaucher disease
New enzymes are not generic and developed as “novel” proteins (biosimilars)

17. Comparison of different enzyme preparations
Imiglucerase
Cerezyme
Velaglucerase
VPRIV
Taliglucerase
Uplyso
Company
Genzyme
Shire-HGT
Protalix-Pfizer
Source
Mammalian
Human
Plant
Structure
Differs one aminoacid from human enzyme
Same as human enzyme structure
Sugar attachments
Chitobioso core glycan (fucosylation)
(requires a second step)
High mannose type (nine mannose residues)
(requires a second step)
Plant -type high mannose residues , more consistent glycosylation
(no modification)
Safety
Antibodies 15 %
6.6 reactions
1 in 54 naïve subjects developed antibodies
Antibodies 8%
6% reactions

18. New enzyme preparations for Gaucher disease
Re-evaluate indications and initiation of ERT in both naïve and switch patients
Management of patients that fail to respond to other ERT products
Cost-benefit maintenance therapy

19. Oral enzyme therapy for Gaucher disease
Oral delivery of enzyme in a solution
Plant cellulose wall protect against degradation
Rats fed with carrot cells expressing enzyme accumulated active enzyme in liver and spleen
Phase 2 (early) studies are underway

20. Small molecule therapies in Gaucher disease
Smaller molecular size allows it to easily penetrate affected cells
Uses the available enzyme in the cell
Decrease the amount of accumulated abnormal lipid
Increase the function of the enzyme (Enyzme Enhancement or Chaperone Therapy)

21. Eliglustat Tartrate- Cerdelga
Glucocerebroside + H20
Ceramide + Glucose
Glucocerebrosidase
Eliglustat tartrate is an analogue for ceramide (basic structure resembles ceramide, the accumulated lipid)
As a substrate synthesis inhibition therapy, eliglustat tartrate slows the body’s production of fatty substances so they do not build up in cells.

22. Pharmacogenomics
Study of genetic factors related to individual variability for response to a drug
In many patients , certain drugs do not work well as expected, and in some cause side effects even at lower doses
Cerdelga® is one of the unique examples, that by labeling pharmacogenomic testing is mandated by the FDA for dosing
Genetic diversity of cytochrome P450 substrates
CYP2D6 is required for critical step in metabolic activation of multiple drugs
Extensive, intermediate, ultra-rapid and poor metabolizers

23. Pharmacogenomics: Why drugs do not work in some patients?
Kitzmiller et al, 2011 Clev Clin J Med

24. Kitzmiller et al, 2011 Clev Clin J Med

25. Drugs that inhibit CYP2D6 (can reduce the effects of Cerdelga®, or pain medication/codeine)
Kitzmiller et al, 2011 Clev Clin J Med