Advances in gaucher disease priya kishnani modified

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Advances in gaucher disease priya kishnani modified

  1. 1. Advances in Gaucher Disease:The Past, Present and Future Priya S. Kishnani, Division Chief, Medical Genetics, Duke University Medical CenterMetabolic Liver Disease MeetingMumbai, Jan 13-14, 2012 *
  2. 2. The Metabolic Defect In Gaucher DiseaseDiagnostic Test : Measurement of leucocyte glucocerebrosidase activity
  3. 3. The Gaucher Cell
  4. 4. Comparative Frequencies of Inherited DiseasesLSDs* 1/7,700Gaucher - AJ 1/850Gaucher - Non-Jewish 1/40,000Cystic fibrosis 1/2,500PKU 1/14,000(hypothyroidism) 1/3,500*Meikel et al, JAMA, 1999,281,249
  5. 5. Clinical Type 1 Gaucher Heterogeneity Asymptomatic Mildly affected Severely affected80-year-old man young adult 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 DiseaseEuropean, US and Israeli type of Gaucherdiseasemajority Type 1, rarely type 2 or type 3Other area’s in the world such as Asia, Africahave more neurologic Gaucher Diseaseneuroprotective N370S mutation not observedor rare
  9. 9. Natural History Organ TissueEnzyme Lipid Infiltration DamageDeficiency Storage With Storage Inflammation Cells Infarction Asymptomatic Symptomatic Fibrosis Organomegaly Organomegaly 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 splenectomyRE 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 PhenotypeN370S/other Type 1Gaucher allele Type 2/3L444P/L444P
  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 paradigmsPrecursors Substrate X (Products) Missing enzyme Toxic products (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 Pretreatment Post-treatment Age 8 Years, 8 Months Age 10 Years, 10 Months
  21. 21. Long Term Response To ERTIn 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 indicatorsWeinreb et al, ICGG, American J Med, 2002
  22. 22. Impact of ERT On Natural History of Gaucher DiseaseCauses of premature deaths in pre-ERT era :• Bleeding • Liver failure • Infection • Crippling bone disease • Pulmonary hypertension ?• Cancers – multiple myeloma ?Problems eliminated by ERTRE Lee, Prog Clin Biol Res, 1981, 95, 177-215
  23. 23. 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 220Platelet 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
  24. 24. 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-<12Hemoglobin (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
  25. 25. Reduction Of Spleen Volume By ERT 0 –10 –20Mean 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
  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 splenomegalyPlease see accompanying full prescribing information. For more information, visitwww.cerezyme.com or call Genzyme Medical Affairs at 1-800-745-4447.
  27. 27. COMPREHENSIVE TEAM APPROACH Otolaryngologist Radiologist Pulmonologist Hematologist Gastroenterologist Pharmacist Cardiologist Interventional Geneticist NephrologistFamily Practitioner Patient/ Obstetrician Nurse Nutritionist Family Neurologist Genetic Counselor Ophthalmologist Neurosurgeon Case Manager Anesthesiologist Phy/Occ therapist Dermatologist Orthopedic Surgeon Internist Audiologist Copyright 2005
  28. 28. Treatment Paradigms SRT ERT Substrate inhibitor UDP-Glucose + GAUCHER UDP-Glucose + Ceramide Ceramide Glucosylceramide Glucosylceramide Glucose + Glucose + Ceramide CeramideModified from the Genetics of Development and Disease Branch / NIDDK / NIH
  29. 29. 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
  30. 30. Proposed Mechanism of Action for Pharmacological ChaperonesPharmacological Chaperone Endoplasmic Golgi Lysosome Reticulum Apparatus Reduced ER Retention Enhanced Trafficking Substrate Clearance Protein-Chaperone Complex Misfolded Protein Substrate Accumulation
  31. 31. Gene replacement therapy- anotherapproach
  32. 32. Some advances in our understanding• Gaucher disease and parkinsonism
  33. 33. Parkinson DiseaseGaucher 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
  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 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 analyzedNagral 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 IndiaAfter 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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