Cystic Fibrosis Update

Transcription

1 Cystic Fibrosis Update More than Decades of Discovery Dr. Raj Padman Professor of Pediatric TJU Board certified in Pediatrics, Pulmonology, and Sleep Medicine Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

2 Road Map History of Cystic Fibrosis The genetics of Cystic Fibrosis Clinical manifestation relating to pathophysiology Genotype to phenotype correlation Translational medicine as applied to Cystic Fibrosis

3 Cystic Fibrosis Most common serious autosomal recessive disease Highest incidence in people of northern European Extraction- 1/3, 300

4 Historical Aspects Carrier rate of 5% Cystic Fibrosis is not a new disease First described in 1930 Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

5 Reference In Early Folklore Literature Schmidt folk philosophy salty taste meant a child was bewitched 1800 Pfyffer-Dictionary of Swiss and German language If it tastes salty when someone is kissed on the brow, then this person is hexed. Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

6 Cystic Fibrosis Rokitansky earliest description of meconium ileus, perforation and peritonitis Fanconi published first paper on CF. Described two children with bronchiectasis and pancreatic insufficiency Anderson published first comprehensive description of 49 patients with CF of the pancreas. Related it to Coeliac Disease Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

7 Cystic Fibrosis Farber generalized disease of the exocrine glands with inspissation of mucous secreting gland mucoviscidosis DiSant Agnese demonstrated an abnormally high level of sodium chloride in sweat Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

8 Cystic Fibrosis African Americans 1/16, 800 Hispanics 1/9, 600 Asians 1/12, 000 Orientals in Hawaii 1/90, 00 Orientals in Great Britain 1/10, 000 Cases reported from Africa and Saudia Arabia Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

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17 Survival CF Life Expectancy

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19 Cystic Fibrosis Gene Isolated Lap Chi Tsui, Toronto Sick Children; Francis Collin-Ann Arbour, Michigan Chromosome 7q31; large size contain 27 exons; 250,000 base pairs >850 mutations identified 70% mutation deletion of three base pairs on tenth exon, loss of a single amino acid phenyl alanine at position 508 referred to as delta F508. Codes for cmp mediated chloride channel-cftr.

20 Site of CF Gene

21 F508 Mutation

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23 Four Classes of CFTR Mutation Causing CF Class 1-defective protein production. Results from nonsense, frame shift due to insertions, deletions and splice site abnormalities Class II- defective processing. Most common CF mutation (delta F508) misfolded do not progress through biosynthetic pathway to cell membrane. Retained and degraded in endoplasmic reticulum Class III- defective regulation despite correct cellular localization, mutation in nucleotide binding domain. Channel opens less frequently. Abnormal response to ATP. Class IV- defective conduction, mutation in membrane spanning domain. Channel Correctly localized, normal regulation. Amount of concurrent is reduced.

24 Four Classes of CFTR Mutations Causing CF

25 Molecular Consequences of CFTR Mutations

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27 Genotype Phenotype Relationships

28 Effectors of CFTR Phenotype

29 Mapping the CF Modifier Genes in Mouse

30 CFTR Mutations in Other Diseases Congenital bilateral absence of vas deferens (CBAVD) Obstructive Azoospermia Chronic Obstructive Pulmonary Disease (COPD) Diffused Bronchiectasis Allergic Broncopulmonary Aspergillosis Chronic Pseudomonas Bronchitis Chronic Bronchial Hypersecretion Chronic Sinusitis Pancreatitis Asthma

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32 Cystic Fibrosis: Pathogenesis and New Therapies

33 Cystic Fibrosis Generalized Multi-Organ System disease from a single biochemical abnormality

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36 Major Pathogenic Events in CF Lung Disease

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39 Mucociliary Clearance And Obstruction Periciliary Liquid (PCL) CFTR normal Surface Epithelial Cells Tenacious Mucus cytoplasmic CFTR CF

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41 Bronchoscopic Views of Normal and CF Airways

42 Domain Model of CFTR

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45 What s New With CFTR? Intermolecular Interactions: CFTR is Linked to Binding Partners and Regulatory Networks!

46 Intermolecular Interactions Between the C-terminus of CFTR and Regulatory Network are Vital for CFTR Function!

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48 Increased Sulfation of Mucins May Enhance Adherence of P aerugion

49 Incidence of Major Airway Pathogens by Patient Age

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51 Neutrophil Phagocytosis

52 Release of Elastase and Oxidants by Neutrophils

53 BALF From CF and Non-CF Infants

54 Airway Inflammation in CF: Neutrophil-Dominated

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56 Neutrophil-Mediated Inflammation in CF Lung Disease

57 Impairment of Complement-Mediated Phagocytic Host Defenses in CF

58 Other Harmful Effects of Neutrophil Elastase

59 Epithelial- Cell Cytokines and Inflammation in CF

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61 CF Air Way Pro Inflammatory Mediators State Of Chronic Inflammation TNF-α,IL-1β,IL-6,IL-8,IL-17,IL-33.GM-CSF,G-CSF,HMGB-l TNF-α enhances neutrophil oxidative and secretory responses promotes cachexia associated with CF IL -1β- induces fever, stimulates acute phase responses promotes muscle protein catabolism TNF α and IL- 1β prime neutrophils, increasing their response to chemo attractants, surface expression of adhesion molecules CD11/CD18, ICAM-1 on endothelial cells GM-CSF delay neutrophil apoptosis and inhibit clearance of neutrophils from lung Pro inflammatory mediators integral component of inflammatory cascade

62 Complex Dysregulated Inflammatory Response In CF Involves multitude of stimuli, cells, signaling pathways transcription factors and products Most research in CF air way inflammation increased activation of inflammatory response Inability to terminate and resolve inflammation also plays a critical role CF air ways deficient in counter regulatory molecules IL-10, nitric oxide [NO].lipoxin-A2 [LXA2]

63 Anti Inflammatory Path Ways Inability To Terminate & Resolve Inflammation IL-10 terminates acute inflammatory response, down regulates production of pro inflammatory cytokines and chemokine's, inhibits pro inflammatory transcription factors induces neutrophil apoptosis T cell clones from CF patients compared to control produce less IL 10 after stimulation Decreased NO exacerbate abnormal ASL height, impair the ability of ASM to relax contribute to bronchial obstruction inhibit bacterial killing & promote inflammation Lipoxin-A4 lipid mediator promotes resolution of neutrophilic inflammation- reduced in stable CF pts. BAL fluid As important as pro inflammatory pathways

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67 Bronchiectasis

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70 Immune Hyperresponsiveness in CF Airways

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76 Potential Drug Therapies for CF

77 CFF Drug Development Programs

78 Therapeutic Approaches to CF

79 Five-Year Actuarial Survival After Lung Transplantation as a Function of Diagnosis

80 Improving Antimicrobial Activity in the CF Airway Inhaled tobramycin- Tobi (Pathogenesis/Chiron) RSV Vaccine- (wyeth-lederle, P. Hiatt et al) Multicenter trial Potential for short and long term reduction in morbidity Dextran- (D. Speert et al)- Multiple actions including: interference with Pseudomonas attachment to epithelium. Xylitol- (J. Zabner et al) 5 carbon sugar, improves antimicrobial properties of airway surface liquid.

81 Improving Mucociliary Clearance in CF Airway Secretion Clearance Study (American Biosystems Inc. CFF) Comparison of Conventional Chest Physical Therapy, Flutter Device, and high Frequency Chest Wall Oscillation 22 centers Inhaled Hypertonic Saline Disrupts ionic bonds in airway secretions Multicenter trial in Australia (P. Bye et al) Purinergic Agonists- (Inspire Pharmaceuticals Inc.) Active alternative chloride channel Increase Ciliary activity Phase I trial (P. Noone et al)

82 Modulating Airway Inflammation in CF Dornase alfa- Pulmozyme (Genetech Inc.) Does early administration of rhdnase slow the decline in lung function? Multicenter, International Trial Elastase Inhibitors Recombinant alpha-one-antitrypsin (PPL Therapeutics plc) DMP 777- specific intracellular inhibitor rmnei- Monocyte/Neutrophil Elastase Inhibitor (CBRI)

83 Enzyme Therapy for CF Airways Secretions- Dornase Alfa: Overview

84 This history is off to a great start Gene therapy for CF will work Additional experiments in humans are needed Progress in other areas will impact on gene therapy for CF Dupont, Kosciusko Community, Lutheran, Rehabilitation, St. Joseph and The Orthopedic hospitals are owned in part by physicians.

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88 Approaches to Gene Therapy of CF

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90 Gene Therapy for CF Will Work but at the present, it does not work well enough

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95 Towards Personalized CF Care: Genomics and Proteomics

96 Spanning the Globe Working Together

97 Cystic Fibrosis Encouraging Developments From The World Of Translational Medicine

98 Translational Medicine: Often described as an effort to carry scientific knowledge from bench to bedside, translational medicine builds on basic research advancesstudies of biological processes using cell cultures, for example, or animal models and uses them to develop new therapies or medical procedures.

99 Translational Medicine: Applied to Cystic Fibrosis: The development of new therapies directly related to the underlying mechanisms of disease that have been discovered in the laboratory

100 What Might Protein Repair Therapy for CF Look Like? Vocabulary 101: - CFTR corrector: Allows mutant CFTR to properly fold and locate to the cell membrane - CFTR potentiator: Improves CFTR function to allow chloride conductance

101 Reduced Quantity Reduced Function Normal CFTR quantity and function Little to no CFTR Some CFTR Gating Conductance Treatment approaches Class I Class II Correctors Class V Class III Class IV Potentiators MacDonald et al. Pediatr Drugs 2007;9:1-10; Zielenski. Respiration 2000;67:117-33; Welsh et al. Cystic fibrosis In: Valle et al, eds. OMMBID. McGraw-Hill Companies Inc;2004:part 21,chap 201; O Sullivan et al. Lancet 2009;373:

102 Mucociliary Clearance And Obstruction Periciliary Liquid (PCL) CFTR normal Surface Epithelial Cells Tenacious Mucus cytoplasmic CFTR CF

103 Lumacaftor Increases The Amount of F508del-CFTR at The Cell Surface Cultured F508del/F508del-human bronchial epithelial cells cilia CFTR nuclei untreated + lumacaftor Van Goor et al., PNAS 2011

104 Protein Repair Candidates Related to Genetic Classes of CFTR Mutations: Medications Recently Approved or In Clinical Trials: Ataluren: Class I mutations (W1282X) Orkambi: Class II mutations (F508del) Recently approved by FDA as Lumicaftor in combination with Ivacaftor (Kalydeco) in homozygous F508del CF patients Kalydeco: Class III mutations (G551D) FDA approved March 2012 and February 2014 for additional Class III mutations Kalydeco: Class IV mutations (R117H) FDA approved December 2014 Symdeko: Tezacaftor/Ivacaftor and Ivacaftor-2018 Class llmutations F508del homozygous and 26 other CFTR mutations sensitive in vitro to this combination

105 CFTR Potentiator for G511D Ivacaftor post approval observational studies 10 % improvement in FEV1 55 % reduction in exacerbations 2.7 Kg weight gain Pronounced CFTR functional improvement Restore 30 to 50 % of CFTR activity in HBE cells Mean sweat chloride of a change in 48.1 mmol/l Long term follow up persistent improvement in exacerbation frequency, rate of pulmonary decline by 50 % from -1.72% control -0.91% /year in treated group Improve mucus clearance and GI Ph, reduce pseudomonas isolation, causes bronchodilatation, reduce structural lung disease Improvement in bacterial load, host defense -potentially reverse structural lung damage turn back the clock

106 Symdeko For Delta F508 Homozygous Lung functions- 4.0 % improvement compared to placebo Pulmonary exacerbation 35 % reduction vs placebo BMI kg/m2 vs placebo not statistically significant CFQ-R respiratory domain 5.1 % increase vs placebo

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111 References Vertex Pharmaceuticals Incorporated, de Jong PA, Et al. Eur Respir J. 2004; 23(1):93-97