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Disorders of Cholesterol Homeostasis

Disorders of Cholesterol Homeostasis. Niemann-Pick disease, type C. Autosomal recessive, progressive, lethal, neurodegenerative disorder due to mutation of either NPC1 or NPC2 Endolysosomal storage of unesterified cholesterol and lipids Incidence: 1/100,000-120,000

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Disorders of Cholesterol Homeostasis

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  1. Disorders of Cholesterol Homeostasis Niemann-Pick disease, type C • Autosomal recessive, progressive, lethal, neurodegenerative disorder due to mutation of either NPC1 or NPC2 • Endolysosomal storage of unesterified cholesterol and lipids • Incidence: 1/100,000-120,000 • No FDA approved therapies

  2. Variable phenotype and age of onset Classical Disease: Late-infantile and juvenile (60-70%) Infantile (20%) Adult Late-infantile and juvenile (classical) Transient neonatal jaundice Splenomegaly Neurological symptoms (insidious onset) Vertical supranuclear ophthalmoplegia Cerebellar ataxia and dysfunction Cognitive impairment and dementia Gelastic cataplexy Seizures Niemann-Pick Disease, type C1

  3. Niemann-Pick Disease, type C1 • Therapeutic trial issues • Rare Disease • Heterogeneous phenotype • Variable age of onset • Variable symptom complex • Clinical progression occurs over years • Goal: Stabilization or delay of neurological disease • Optimal treatment may be prior to the onset of neurological signs and symptoms • Significant diagnostic delay • Lack of defined and accepted outcome measures

  4. Natural History Trial 78 patients enrolled since August 2006 Age range: 3 months to 54 years (median 10 years) NPC1 Neurological Severity (range 0-50, median 14) Miglustat therapy (42%) Goals: Identify clinical or biochemical markers that can be used as an outcome measure in a therapeutic trial Identify a biochemical marker that can be used for diagnostic testing or screening 40 Severity Score 20 0 10 20 30 40 50 Age (years) Niemann-Pick disease, type C1

  5. Niemann-Pick Disease, type C1 Mean Diffusivity Volume

  6. Niemann-Pick Disease, type C Biomarker Development (Assembling a Tool Box)

  7. Niemann-Pick disease, type C1 • Biomarkers • Insight into pathology • Diagnostic/screening test • Tools to guide therapeutic trials • Biomarker identification • Candidate proteins/lipids • Multi-analyte profiling • Expression analysis • Proteomics

  8. Oxysterols Blood-based diagnostic test

  9. Filipin Staining Fluorescent antibiotic that binds unesterified cholesterol Specialized testing Requires a skin biopsy-invasive Variable staining 80-85% “classical” Molecular Testing Expensive and requires a high index of suspicion ~80% sensitive 4-5 year diagnostic delay Filipin Staining Control NPC Vanier and Millat (2003) Clin Genet. 64: 269-281 Niemann-Pick Disease, type C Dan Ory (personal communication)

  10. NPC1: Clinical Science TEAC (mM) p<0.0001 n=40 n=40 Control NPC Intracellular Cholesterol Accumulation in NPC1 Decreased Serum Antioxidant Capacity in NPC1 Subjects • Oxysterols • Hypothesis: In NPC1 the unique combination of increased oxidative stress and intracellular accumulation of unesterified cholesterol will result in increased nonenzymatic oxysterols. Fu et al (2010) MGM, 101:214

  11. Niemann-Pick Disease, type C1 • 3β,5α,6β-cholestane-triol • 7-ketocholesterol Plasma Oxysterols3β,5α,6β-cholestane-triol 7-ketocholesterol Porter et al. (2010) STM, 2: 56ra81

  12. Niemann-Pick Disease, type C1 Triol (24.5 ng/ml) Sensitivity 97% Specificity 100% Porter et al. (2010) STM, 2: 56ra81 Jiang et al. (2011) JLR, 52:1435

  13. Niemann-Pick Disease, type C1 CSF Protein Biomarkers

  14. Niemann-Pick Disease, type C1 Calbindin D +/+ -/- p<0.001 p=0.28

  15. Niemann-Pick Disease, type C A B C D Untreated B/A Treated D/C Pre/post C/B Miglustat

  16. Niemann-Pick disease, type C1 Fatty Acid Binding Protein 3 (FABP3) 62 62 59 59 Npc1+/+Npc1-/- CSF p<0.0001 p<0.0001 p=0.05

  17. Niemann-Pick disease, type C1 Macrophage Inflammatory Protein 1-alpha (Mip1α, CCL3) Proinflammatory cytokine Activated microglia p<0.0001 CSF Control 4.8 ± 1.9 pg/ml NPC 14.7 ± 4.2 Confidential

  18. CSF Biomarkers CSF Biomarkers Lipid-based 3β,5α,6β-cholestane-triol and cholesterol esters Protein-based Markers of inflammation MIP-1α, IL1a, IL3, IL4, IL12p40, IL13, IL15, and MMP2 Markers of neuronal injury Aβ(42), phosphorylated tau, fatty acid binding protein 3 (FABP3), and calbindin-D Markers of oxidative stress glutathione S-transferase alpha (GSTα) and superoxide dismutase 1 (SOD1)

  19. 2-Hydroxypropyl-β-cyclodextrin

  20. NPC1 HPβCD Trial • 2-Hydroxypropyl-β-cyclodextrin (HPβCD) • Cyclic oligosaccharide with a hydrophobic core • Pharmaceutical excipient • Drug repurposing

  21. NPC1 HPβCD Trial Npc1 mouse model Survival Npc1+/+ Npc1-/- Npc1-/- + CD Cerebellar pathology: 49-days Ramirez et al. (2010) Ped. Res. 68: 309 Liu et al. (2009) PNAS 106: 2377

  22. NPC1 HPβCD Trial Npc1 cat model 24 week Npc1 mutant cats (HPβCD, miglustat, untreated) Personal Communication: Charles Vite

  23. NPC1 HPβCD Trial • HPβCD Therapeutic trial • Pilot project for TRND/NCATS • Goal: Improve drug development for rare and neglected diseases • HPβCD does not cross the blood-brain barrier • Dose limiting toxicity: Ototoxicity • Cat, dog, and mouse

  24. NPC1 HPβCD Trial Lancet (1963) 282: 983-984 Risks Bleeding/strokes Infection Seizure

  25. NPC1 HPβCD Trial • Phase 1 trial • Goal: Establish a safe and biochemically effective dose • Cohort dose-escalation • Safety • Pharmacokinetics • Quantitative and validated assay for HPβCD • Pharmacodynamics (Biochemical efficacy) • Quantitative and validated assays for 24-hydroxycholesterol • Pathological efficacy • CSF protein and lipid biomarkers

  26. NPC1 HPβCD Trial NPC1 • Pharmacodynamic response • Plasma 24(S)-hydroxycholesterol Neuron Cholesterol Synthesis ApoE C HPβCD CYP46 24(S)HC CSF Blood 24(S)HC

  27. NPC1 HPβCD Trial NPC1 • Pharmacodynamic response • Plasma 24(S)-hydroxycholesterol Neuron Cholesterol Synthesis ApoE C HPβCD CYP46 24(S)HC CSF Blood 24(S)HC

  28. Saline HPβCD CSF and Plasma Sampling (0 to 72 hours) CSF and Plasma Sampling (0 to 72 hours) NPC1 HPβCD Trial • Baseline standard deviation of the saline area under the curve (AUC) estimated by resampling (bootstrapping) • Biochemical response defined as: • In an individual patient the difference between the drug and saline AUC greater than 2.3 x SD is considered a positive response • Positive response observed in at least 2 out of 3 patients

  29. NPC1 HPβCD Trial • 50 mg HPβCD • No drug related adverse events or reactions • 2/3 patients had a biochemical response • AUC8-72 • Patient 1 + 3.1 x sd • Patient 2 + 0.8 x sd • Patient 3 + 4.1 x sd • P. acnes • Infection/Colonization

  30. Niemann-Pick disease, type C1 • ICV versus lumbar IT • Dose escalation response • Repetitive dosing response: Attenuation • Response of other biomarkers • Safety-Ototoxicity

  31. Cohort Dose-escalation STOP Cohort 1 50 mg Dose Not Tolerated Not Tolerated Tolerated No Response Tolerated No Response Cohort 1/2 200 mg Dose Cohort 1/2/3 300 mg Cohort 3/4 400 mg Tolerated Biochemical Response Tolerated Biochemical Response Tolerated Biochemical Response Cohort 1/2 Maintain 200 mg Maintain 300 mg Maintain 400 mg Cohort 3

  32. Niemann-Pick disease, type C1 • No significant response at 50 and 200 mg IT • Positive response in 2/3 subjects at 300 mg IT • Response similar to 50 mg ICV • Grade 1 Ototoxicity in 2 subjects (siblings) • 400 mg cohort completed this week

  33. Niemann-Pick disease, type C1 • Clinical efficacy trial • Multicenter: Funding and IRB complexity • Multinational: Funding, IRB and regulatory complexity • NeuroNext Network • Concept proposal accepted • Clinical outcome measures • Ataxia (Cerebellar Function) • Gross motor • Fine motor • Swallowing • US Sites • Common IRB • Common Trial Agreement

  34. NPC1 HPβCD Trial • HPβCD selected as a TRND clinical candidate in February 2011 • PreIND meetings with FDA in October and December 2011 • Juvenile dog toxicity study, formulation, and device compatibility studies performed in 2012 • IRB approval July 2012 and IND filing November 2012 • First ICV infusion February 4, 2013 • First IT infusion September 28. 2013

  35. NPC1 TRND Team NICHDWashington University School of Medicine Nicole Yanjanin Daniel Ory Aiyi Liu (DESPR) Roopa Shankar University of Pennsylvania NHGRI Charles Vite Bill Pavan NINDS Albert Einstein Collage of Medicine Russell Lonser Steven Walkley John Heiss TRND/NCATSJohnson and Johnson SAIC/Leidos Chris Austin Steven Silber Jon Stocker John McKew Mark Kao Molly Buehn Nuria Carrillo Marcus Brewster Leah Giambarresi Liz Ottinger Juan Marugan RRD International Pramod Terse Charles Finn Patrick Frenchick Xin Xu Frank Hurley Sandra Morseth Wei Zheng Joy Vanderwal Kimberly Lilly Clinical Center Carmen Brewer Beth Solomon Naomi O’Grady Kelly King

  36. Acknowledgements SMD, PDEGEN, NICHD Nicole Yanjanin Lee Ann Knight Roopa Shankar Chris Wassif Celine Cluzeau Stephanie Cologna Ryan Lee Cynthia Toth Jiang Xiao-Sheng Ian Williams Antony Cougnoux ORD/CC Bench to Bedside Awards Ara Parseghian Medical Research Foundation National Niemann Pick Disease Foundation SOAR-NPC Dana’s Angels Research Trust

  37. Niemann-Pick disease, type C1

  38. Niemann-Pick disease, type C1

  39. Hydroxypropyl-β-Cyclodextrin Mouse Cat Mouse 0.5 g Cat 30.0 Human 1400.0 Newborn 375.0

  40. Vertical supranuclear ophthalmoplegia • Differential • -Niemann-Pick Disease, type C1 • -Progressive Supranuclear Palsy • -Midbrain lesions Niemann-Pick Disease, type C1

  41. Niemann-Pick disease, type C1 Attenuation of the 24OHC response with repetitive dosing

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