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Gaucher disease past present future

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Gaucher disease past present future

  1. 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. 2. The Metabolic Defect In Gaucher Disease Diagnostic Test : Measurement of leucocyte glucocerebrosidase activity
  3. 3. The Gaucher Cell
  4. 4. 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
  5. 5. Type 1 Gaucher Asymptomatic 80-year-old man Mildly affected young adult Clinical Heterogeneity Severely affected girl
  6. 6. Acute Neuronopathic Gaucher Disease (Type 2) • Strabismus • Retroflexion of the neck • Cortical thumbs • Visceromegaly • Failure to thrive • Cachexia
  7. 7. Type II-Neuropathology • Glucocerebroside accumulates in brain • Brainstem accumulation common • Brainstem nuclei affected
  8. 8. 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
  9. 9. Natural History Enzyme Deficiency Organ Lipid Infiltration Storage With Storage Cells Asymptomatic Symptomatic Organomegaly Organomegaly Tissue Damage Inflammation Infarction Fibrosis Splenectomy Morbidity Premature death
  10. 10. 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
  11. 11. Gaucher Disease – a Continuum of Phenotypes
  12. 12. Other Phenotypes • Hydrops fetalis may be rarely seen
  13. 13. Cancer & Gaucher Disease • Lymphoproliferative disorders more common in Gaucher patients – chronic lymphocytic leukemia – multiple myeloma – non-Hodgkin lymphoma • Bone tumors • Multiple myloma
  14. 14. Gaucher Genotypes
  15. 15. Genotype/Phenotype Correlations Genotype N370S/other Gaucher allele L444P/L444P Phenotype Type 1 Type 2/3
  16. 16. 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
  17. 17. 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)
  18. 18. Treatment paradigms Precursors Substrate Toxic products X (Products) Missing enzyme (Deficient downstream products)
  19. 19. 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
  20. 20. Response to Enzyme Therapy Pre-treatment Age 8 Years, 8 Months Post-treatment Age 10 Years, 10 Months
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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.
  27. 27. COMPREHENSIVE TEAM APPROACH Radiologist Otolaryngologist Pulmonologist Hematologist Gastroenterologist Pharmacist Cardiologist Family Practitioner Neurologist Nurse Patient/ Family Copyright 2005 Ophthalmologist Case Manager Phy/Occ therapist Obstetrician Nutritionist Genetic Counselor Neurosurgeon Orthopedic Surgeon Nephrologist Interventional Geneticist Anesthesiologist Dermatologist Internist Audiologist
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. Gene replacement therapy- another approach
  32. 32. Some advances in our understanding • Gaucher disease and parkinsonism
  33. 33. 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
  34. 34. 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
  35. 35. Gaucher Disease • ? Parkinsonism How are these two disorders related?
  36. 36. Brain samples show Lewy bodies, inclusions characteristic of Parkinson disease and related disorders. H&E, 400X -Synuclein antibody, 200X
  37. 37. 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.
  38. 38. 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.
  39. 39. Acknowledgements • • • • • Colleagues at Duke University Colleagues in India Colleagues from ICGG Pramod Mistry, MD Most importantly our patients who teach us everyday

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