Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics...

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Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics University of California San Francisco

Transcript of Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics...

Page 1: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Gaucher Disease: Problems, Solutions, and

Problems

Seymour Packman, MD

Department of PediatricsDivision of Medical GeneticsInstitute for Human Genetics

University of California San Francisco

Page 2: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.
Page 3: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Gaucher Disease Type 1: Pathophysiology

Deficiency of the lysosomal enzyme acid β-glucosidase

Storage of glucosylceramide primarily in cells of the monocyte/macrophage lineage

Progressive, multi-organ dysfunction primarily involving the reticulo-

endothelial system

Gaucher Cell

Grabowski et al. MMBID Online. 2013.

GMRB-0125-01

Page 4: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Clinical Manifestations of Gaucher Disease Type 1

• Massive splenomegaly

• Cytopenia• Hypermetabolic

state: fatigue

• Infiltrative lung disease

• Avascular osteonecrosis• Osteoporosis• Pathological fractures• Chronic bone pain

• Hepatomegaly

• Marrow infiltration

• Cytopenia

Reflect Cellular Sites of Substrate Accumulation

Grabowski et al. MMBID Online. 2010.

Lung

Alveolar macrophages

Spleen

Tissue macrophages

Osteoclasts

BoneLiverKupffer cells

(Hepatocytes spared)

Bone marrow

Monocytes

Macrophages

Page 5: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Gaucher Clinical Presentation

Charrow J et al., Arch Intern Med. 2000;160:2835.

Clinical Involvement

Patients with GD1 can present with any of these symptoms.

Some may be severe and others completely absent.

Pathologic fracture (15%)

Osteonecrosis (25%)Osteopenia (42%)

Anemia (64%)Thrombocytopenia (56%)

Erlenmeyer flask deformity (46%)

Hepatomegaly (79%)Splenomegaly (87%)

Bone pain (63%)Bone crisis (33%)

Joint collapse (8%)

General symptoms:• Fatigue• Easy bruising/bleeding• Menorraghia • Decreased appetite• Abdominal pain

Bone marrow infiltration (40%)

GMRB-0125-01

Page 6: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Milestones in Gaucher Disease Treatment

1990 2000 2010

1985: Glucocerebrosidase gene (GCB) cloned1 and mapped to chromosome 1q211,2

First recombinant human glucocerebrosidase ERT approved in US (Cerezyme®) in 1994 and in EU in 1997

1991: First placental-derived glucocerebrosidase ERT approved in US and EU (Ceredase ® )

1983: First patient with GD1 treated at NIHwith glucocerebrosidase purified from human placenta

2011: Placebo- controlled trial of eliglustat completed in treatment-naïve GD1 patients

20121980

2003: IND filed for GZ-112638 (eliglustat)

2003: First SRT approved in patients with GD1 for whom ERT is not an option (Zavesca®)

IND=Investigational New Drug; ERT= enzyme replacement therapy; GD1=Gaucher disease type 11. Sorge. PNAS, 1985:82:7289; 2. Ginns, PNAS 1985;82:7101.

Page 7: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Approved Treatments for Gaucher Disease

– Alglucerase (Ceredase®); purified human placental enzyme. • Approved in 1991; no longer available

– Imiglucerase (Cerezyme®); recombinant human enzyme; produced in CHO cells.

• Approved in 1994.– Velaglucerase alfa (Vpriv®, Shire); recombinant human

enzyme, produced in human cells. • Approved in 2010.

– Taliglucerase alfa (ElelysoTM, Pfizer/Protalix), recombinant human enzyme, produced in carrot cells

• Approved in 2012 GMRB-0125-01

Page 8: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

ENZYME REPLACEMENT THERAPY

• Replacement of defective enzyme with normal genetically engineered enzyme

• Engineered enzyme is tagged with a specific recognition signal for delivery to appropriate cell or organelle

• Administration by intermittent IV

Page 9: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Rough ER

P

Cis Golgi

P

Trans Golgi

Lysosome

P

Mannose-6-Phosphate ReceptorSystem

P = Mannose-6-P

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GAUCHER DISEASE

• Enzyme Replacement Therapy hemoglobin in a few months

platelets

organomegaly in ~ 6 months

bone pain, bone crises

Slow change of bone X-ray abnormalities

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Page 13: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.
Page 14: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.
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Page 16: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Approved Treatments for Gaucher Disease

• Substrate reduction therapy (SRT); oral administration– Zavesca® (miglustat, Actelion); imino sugar-based analogue

• Approved in 2003. • Indicated only for adults with mild to moderate Gaucher

disease who are unable or unwilling to receive ERT– Cerdelga ® (eliglustat, Genzyme); ceremide-based analogue

• Approved in 2014• Indicated for the longterm treatment of adult patients with

Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by a genetic test

GMRB-0125-01

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Synthesis (S) & Degradation (D) of glucosylceramide (GL-1)

Normal Gaucher GaucherGaucher Disease + ERT + SRT

S D S SSD D D

For graphic illustration purposes only.ERT=enzyme replacement therapy; SRT=substrate reduction therapy.Shayman. Drugs Future. 2010:35:613.

Restoring a Balance Between GL-1 Substrate Synthesis and

Degradation

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Zavesca (miglustat)

• Effective in Gaucher treatment• FDA approved if cannot use ERT• Adverse reactions:

- peripheral neuropathy (tingling, numbness, burning)

- tremor (30%)- diarrhea (85%; reduce high CHO)- mild weight loss (65%)

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miglustat

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Eliglustat (Cerdelga) Mechanism of Action

Glucosylceramide Synthase

Acid β-glucosidaseDeficient in Gaucher disease

Eliglustat

Ceramide + Glucose Glucosylceramide

Enzyme Replacement Therapy

Shayman. Drugs Future. 2010:35:613.

GMRB-0125-01

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Ver. 10 May2010 23

Eliglustat Tartrate is a Novel Analog of Glucosylceramide

Glucosylceramide Eliglustat tartrate

OH

HNO

OHOHO OH

OHO

N

O

O

O

HN

OH

Page 24: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

Inhibitors of Glucosylceramide Synthase

GMRB-0125-01

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Rough ER

P

Cis Golgi

P

Trans Golgi

Lysosome

P

Mannose-6-Phosphate ReceptorSystem

P = Mannose-6-P

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Chaperones

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Chaperones

Page 28: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

SMALL MOLECULES: CHAPERONES

• Stabilize mutant enzyme

• Increase β-glucocerebrosidase levels in Gaucher patients’ cells

• In development for Gaucher

• In phase III clinical trial for other lysosomal disorders

Page 29: Gaucher Disease: Problems, Solutions, and Problems Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics.

TREATMENT APPROACHES for LYSOSOMAL DISORDERS

• Enzyme replacement• Novel biochemical measures

– substrate reduction– chaperones– other small molecules: regulate

gene expression or protein function; encapsulated cells

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…out of nature’s certain course,A gift that rather was come late than soon.

W. Wordsworth

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