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Cystic fibrosis, existing and emerging therapies

Cystic fibrosis, existing and emerging therapies. Thomas Ferkol MD Markey Pathway Conference. Cystic fibrosis: a historical timeline. 1938. Cystic fibrosis (CF) of the pancreas was described by Andersen.

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Cystic fibrosis, existing and emerging therapies

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  1. Cystic fibrosis, existing and emerging therapies • Thomas Ferkol MD • Markey Pathway Conference

  2. Cystic fibrosis: a historical timeline 1938 Cystic fibrosis (CF) of the pancreas was described by Andersen. The sweat defect was discovered by diSant'Agnese and colleagues when they noticed that many of the infants presenting with heat prostration during the “great summer heat wave” in New York City had CF. Cystic fibrosis was identified as an autosomal recessive disease. The fundamental physiologic defects were clearly established by Knowles and colleagues and Quinton as the failure of cAMP regulation of chloride transport. The genetic defect for CF was located on chromosome 7. The gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was identified by positional cloning. Cystic fibrosis transmembrane conductance regulator was established to be a cAMP-regulated chloride channel by complementation studies. 1953 1965 1983 1985 1989 1990

  3. Cystic fibrosis: clinical presentations • Gastrointestinal • meconium ileus • meconium plug syndrome • distal intestinal obstruction syndrome • rectal prolapse • neonatal hyperbilirubinemia • failure to thrive • hypoproteinemic edema • hypovitaminosis • recurrent pancreatitis • biliary cirrhosis and portal hypertension • Endocrine • diabetes • Genitourinary • male infertility • Sweat Gland Dysfunction • hypochloremic, hyponatremic alkalosis • Respiratory • chronic cough • recurrent sinopulmonary infections • bronchiolitis/asthma • nasal polyposis • Staphylococcus aureus pneumonia • Pseudomonas aeruginosa endobronchitis

  4. Cystic fibrosis: epidemiology Population Caucasian (US) Caucasian (Great Britain) Hispanic African American Native American Asian (US, England) Israel Southern Europe Epidemiologic 1 in 1,900-3,700 1 in 2,400-3,000 1 in 8,000-9,000 1 in 15,300 1 in 40,000 1 in 10,000 1 in 5,000 1 in 2,000-4,000 Newborn screening 1 in 3,400-3,800 1 in 2,200-3,200 -- -- -- -- -- --

  5. Cystic fibrosis: median survival age, 1940-2007 37.8 35 30 25 20 Median survival age (years) 15 10 5 0 2010 1940 1950 1960 1970 1980 1990 2000 Year Cystic Fibrosis Foundation Registry, 2007.

  6. Cystic fibrosis: a historical timeline 1938 Cystic fibrosis (CF) of the pancreas was described by Andersen. The sweat defect was discovered by diSant'Agnese and colleagues when they noticed that many of the infants presenting with heat prostration during the “great summer heat wave” in New York City had CF. Cystic fibrosis was identified as an autosomal recessive disease. The fundamental physiologic defects were clearly established by Knowles and colleagues and Quinton as the failure of cAMP regulation of chloride transport. The genetic defect for CF was located on chromosome 7. The gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was identified by positional cloning. Cystic fibrosis transmembrane conductance regulator was established to be a cAMP-regulated chloride channel by complementation studies. 1953 1965 1983 1985 1989 1990

  7. Cystic fibrosis: airway inflammation Normal Cystic fibrosis Na+ Cl- Na+ Cl- Cl- Cl- ENaC CFTR Cl-a K+ K+ H2O H2O Na+ Na+ Na+ Na+ K+ K+ 2Cl- 2Cl-

  8. Cystic fibrosis: nasal transepithelial potential difference amiloride Cl- free forskolin ATP -60 -50 normal -40 PD (mv) PD -30 -20 CF -10 0 4 6 8 10 0 Time (m)

  9. Cystic fibrosis: a historical timeline 1938 Cystic fibrosis (CF) of the pancreas was described by Andersen. The sweat defect was discovered by diSant'Agnese and colleagues when they noticed that many of the infants presenting with heat prostration during the “great summer heat wave” in New York City had CF. Cystic fibrosis was identified as an autosomal recessive disease. The fundamental physiologic defects were clearly established by Knowles and colleagues and Quinton as the failure of cAMP regulation of chloride transport. The genetic defect for CF was located on chromosome 7. The gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was identified by positional cloning. Cystic fibrosis transmembrane conductance regulator was established to be a cAMP-regulated chloride channel by complementation studies. 1953 1965 1983 1985 1989 1990

  10. Classes of cystic fibrosis-causing mutations ADP ADP Class 4: CFTR mutants that have altered channel properties, e.g., R117H ATP ATP Class 3: regulatory mutants that fail to respond normally to activation signals, e.g., G551D PKA ADP ATP Endosome Class 2: CFTR degradation in the endoplasmic reticulum, e.g., F508 Golgi Class 1: premature termination of CFTR mRNA translation, e.g., S489X ER Class 5: decreased functional CFTR synthesis or transport, e.g., A455E Nucleus

  11. Cystic fibrosis: clinical phenotype associated with CFTR mutations Severe lung disease Pancreatic insufficiency Abnormal sweat chloride Milder lung disease Pancreatic sufficiency Abnormal sweat chloride Mild lung disease Pancreatic sufficiency Equivocal sweat chloride R117H (5T) 3849 + 10kB C-to-T 2789 + 5 G-to-A R334W G85E G91R R347P R347H R347L R117H (7T) 3849 + 10kB C-to-T G551S D1152H A455E F508 G542X G551D W1282X N1303K R553X 3120 + 1G-to-T 1078 del T R75X

  12. Prospects for correcting cystic fibrosis: level of correction Chillon M, et al. N Engl J Med. 1996; 332:1475. Tissue affected CFTR activity 100% (wt, 9T/9T) 50% (wt, 9T, and mutant CFTR) unaffected vas deferens 10% (wt protein, 5T/5T) 5% (wt protein, 5T, and severe mutant) sweat duct airway 4% (R117H, 7T, and severe mutant) 1% (R117H, 7T, and severe mutant) pancreas <1% (G551D, F508)

  13. Pathogenesis of lung disease in cystic fibrosis Defective CF gene Davis PB, et al. J Respir Crit Care Med. 1996;154:1229. Defective/deficient CFTR Abnormal airway surface milieu Bronchial obstruction Infection Inflammation Bronchiectasis

  14. Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Chest physiotherapy Mucolytics (rhDNase) Hypertonic saline Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  15. Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Chest physiotherapy Mucolytics (rhDNase) Hypertonic saline Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  16. Cystic fibrosis: organisms isolated from the lower respiratory tract 100 P. aeruginosa 80 60 Percentage positive S. aureus 40 H. influenzae 20 B. cepacia 0 0-1 2-5 6-10 11-17 18-24 25-34 35-44 >45 Age (y) Data compiled from Cystic Fibrosis Foundation Patient Registry, 2007.

  17. males females Effect of Pseudomonas aeruginosa acquisition in cystic fibrosis Demko CA, et al. J ClinEpidemiol. 1995;48:1041 Late acquisition (>6y) 1.0 0.9 Cumulative survival 0.8 Early acquisition (<6y) 0.7 0.6 6 8 10 12 14 16 Age (y)

  18. Cystic fibrosis: bacterial colonization Impaired mucociliary clearance Impaired antimicrobial activity Antibacterial proteins asialoGM1 CFTR Increased adherence Impaired phagocytosis

  19. Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Chest physiotherapy Mucolytics (rhDNase) Hypertonic saline Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  20. Cystic fibrosis: pathology

  21. Cystic fibrosis: radiological findings

  22. Cystic fibrosis: airway inflammation mac pmn NE TNF-a IL-8 IL-1b O2- respiratory epithelium Normal Cystic fibrosis

  23. Anti-inflammatory agents in cystic fibrosis: corticosteroids • Eigen H, et al. J Pediatr. 1995;126:515. • Lai HC, et al. N Engl J Med. 2000;342:851. • A four year, randomized double-blind, placebo-controlled trial that compared the efficacy of two doses (1 mg/kg/d and 2 mg/kg/d) of alternate-day prednisone therapy with placebo in children with CF. 4 p = 0.0001 3 2 2 mg/kg 1 1 mg/kg 0 6 12 18 24 30 36 42 48 mos -1 FVC (% predicted for age -2 -3 -4 -5 high-dose arm stopped placebo -6

  24. Anti-inflammatory agents in cystic fibrosis: azithromycin • Saiman L, et al. JAMA. 2003;290:1749. • An five-month, randomized, double-blind, placebo-controlled trial that examined the efficacy of azithromycin in patients with CF (age > 6 years, N = 251), chronically colonized with P. aeruginosa, and lung disease (FEV1 > 30% predicted for age). p = 0.009 5 4 3 2 1 azithromycin 0 FEV1 (% predicted for age) days 28 84 168 196 -1 -2 placebo -3 -4 Drug stopped -5 -6

  25. Cystic fibrosis: median survival age, 1940-2007 inhaled mucolytics 37.8 anti-Staphylococcus antibiotics 35 30 airway clearance 25 inhaled antibiotics 20 Median survival age (years) 15 10 anti-Pseudomonas antibiotics 5 0 2010 1940 1950 1960 1970 1980 1990 2000 Year Cystic Fibrosis Foundation Registry, 2007.

  26. Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Amiloride UTP/ATP Hypertonic saline Block Na+ uptake Increase Cl- efflux Abnormal airway surface milieu Mucolytics (rhDNase) Chest physiotherapy Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  27. Cystic fibrosis: alternative therapies to effect bioelectric properties of the respiratory epithelium CF Altering other channels Cl- Na+ Cl- Na+ ENaC ClCa CFTR Amiloride UTP/ATP Hypertonic saline Cl-

  28. Aerosolized hypertonic saline for the treatment of cystic fibrosis Elkins MR, et al. N Engl J Med. 2006;354:229. An 48-week, randomized, double-blind, parallel-group trial that examined the efficacy of inhaled hypertonic saline in patients with CF over 6 years of age. 100 75 p = 0.001 Survival free of symptom-defined exacerbations (%) 9.2 w 36 w 50 hypertonic saline 25 control 0 0 12 24 36 48 Period of observation (w)

  29. Treatment of cystic fibrosis lung disease Defective CF gene VX809 VX770 PTC124 Increase CFTR protein Activate mutant form Defective/deficient CFTR Amiloride UTP/ATP Hypertonic saline Block Na+ uptake Increase Cl- efflux Abnormal airway surface milieu Mucolytics (rhDNase) Chest physiotherapy Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  30. Cystic fibrosis: correcting CFTR dysfunction Zeitlin P. N Engl J Med. 2004;351:606 G551D CFTR F508 CFTR Cell membrane Cell membrane VX770 Endosome Endosome Proteasome apical trafficking degradation Golgi Golgi post-translational folding Low temperature VX809 translation Glycerol ER ER transcription Nucleus Nucleus

  31. Cystic fibrosis: correcting G551D CFTR dysfunction • Accurso FJ, et al. N Engl J Med. 2010;363:1991. • A four-week, randomized placebo-controlled trial that compared the effect of regular treatment with VX770 with placebo in CF patients with G551D mutation. 120 placebo 100 80 [Sweat chloride] (mmol/L) VX770, 150 mg 60 VX770, 250 mg 40 20 0 3 14 21 28 days

  32. Cystic fibrosis: potentiating delF508 CFTR dysfunction • A two-week, randomized double-blind, crossover trial that compared the effect of regular treatment with VX809 with placebo in CF patients with delF508 mutation. 25 50 100 200 0 -2 -4 [Sweat chloride] (mmol/L) -6 -8 -10

  33. Wilschanski M. N Engl J Med. 2003; 349:1433. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations -8 -6 p = 0.03 Response of nasal PD to chloride-free isoproterinol (mV) pre-treatment -4 -2 0 0 0.3 0.6 0.9 1.2 Gentamicin concentration (%) post-treatment

  34. Treatment of cystic fibrosis lung disease Defective CF gene Provide normal gene Gene therapy VX809 VX770 PTC124 Increase CFTR protein Activate mutant form Defective/deficient CFTR Block Na+ uptake Increase Cl- efflux Amiloride UTP/ATP Abnormal airway surface milieu Mucolytics (rhDNase) Chest physiotherapy Hypertonic saline Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

  35. Active or completed human gene therapy protocols Infectious diseases (40) Human immunodeficiency virus (37) Other viral diseases (3) Monogenic diseases (58) Alpha1-antitrysin deficiency (2) Chronic granulomatous disease (3) Cystic fibrosis (23) Familial hypercholesterolemia (1) Fanconi anemia (4) Gaucher disease (3) Hunter syndrome (1) Ornithinetranscarbamylase deficiency (1) Purine nucleoside phosphorylase deficiency (1) Severe combined immunodeficiency disease (6) Leukocyte adhesion deficiency (1) Canavan disease (3) Hemophilia (5) Muscular dystrophy (1) Amyotrophic lateral sclerosis (1) Junctionalepidermolysisbullosa (1) Neuronal ceroidlipofuscinosis (1) Cancer (405) Other diseases(66) Peripheral artery disease (24) Arthritis (4) Arterial restenosis (3) Congestive heart failure (1) Coronary artery disease (21) Alzheimer disease (2) Ulcer (3) Bone fracture (1) Peripheral neuropathy (1) Parkinson disease (2) Eye disorders (4) Erectile dysfunction (1) Intractable pain (1)

  36. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis Crystal RG, et al. Nat Genet. 1994;8:42. Pretreatment In vivo transfection In vitro transfection Pretreatment In vivo transfection In vitro transfection

  37. A controlled study of adenovirus-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis Knowles MR, et al. N Engl J Med. 1995;333:823. CFTR mRNA Patient No. Cohort 1123 Cohort 2123 Cohort 3123 Cohort 4123 MOI111101010 100100100 100010001000 vehicle-treated no no no no no no no no no no no no vector-treatednononononoyesyes no yesyes no yes

  38. A controlled study of adenovirus-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis Knowles MR, et al. N Engl J Med. 1995;333:823. -40 -40 -30 -30 -20 -20 PD (mV) PD (mV) -10 -10 0 0 10 10 -5 0 5 10 -5 0 5 10 Days Days

  39. Effectiveness of current gene transfer vehicles used in cystic fibrosis Gene transfer vehiclesAdenovirusAdeno-associated virusRetrovirus Murine leukemia virus LentivirusCationic liposomesMolecular conjugates DNA deliveryyesyesNDNDyesyes RNA expression yesnoNDND maybe no CFTR functionnonoNDNDnomaybe

  40. Prospects for gene therapy of cystic fibrosis: submucosal gland Engelhardt JF, et al. J Clin Invest. 1994;93:737.  epithelium (+) duct (++++) submucosal glands (++) Sites of CFTR expression in the human airway http://www.medicine.mcgill.ca/dynhist/histoimages

  41. Prospects for gene therapy of cystic fibrosis: obstacles • Respiratory epithelial cells vs submucosal glands. • Unavailable target receptors. • Inability to bypass physical and functional barriers in the airway. • Possible biologic unsuitability of the airway epithelium as a target tissue. • Immunologic consequences. • Relevant outcome measure.

  42. Treatment of cystic fibrosis lung disease Defective CF gene Provide normal gene Gene therapy VX809 VX770 PTC124 Increase CFTR protein Activate mutant form Defective/deficient CFTR Amiloride UTP/ATP Hypertonic saline Block Na+ uptake Increase Cl- efflux Abnormal airway surface milieu Mucolytics (rhDNase) Chest physiotherapy Decrease mucus viscosity Augment clearance Bronchial obstruction Infection Antibiotics Macrolides Decrease bacterial load Corticosteroids Ibuprofen Inflammation Reduce host response Bronchiectasis Replace damaged lungs Transplantation

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