Cystic fibrosis: hitting the target

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1 Cystic fibrosis: hitting the target Heartland Collaborative Annual Meeting Friday, October 5, 2012 Thomas Ferkol MD Cystic fibrosis: a historical timeline 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 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 campregulated chloride channel by complementation studies. 1

2 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 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 2

3 10/8/2012 Cystic fibrosis: pathology Cystic fibrosis: radiological findings 3

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5 Cystic fibrosis: prognosis Involvement of the respiratory tract typically dominates the clinical picture and determines the fate of the patient. Pancreatic function is a strong determinant of outcome. Natural variation in severity of the pulmonary involvement is important in determining the severity of the clinical course. Patients who are nutritionally replete have less morbidity and mortality. Early diagnosis and treatment is effective in prolonging the lives of affected individuals Cystic fibrosis: a historical timeline 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 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 campregulated chloride channel by complementation studies. 5

6 Cystic fibrosis: airway inflammation Normal Cystic fibrosis Na + Cl Cl Na + Cl ENaC Cl CFTR Cl a K + K + Na + Na + K + H 2 O Na + Na + K + H 2 O 2Cl 2Cl Cystic fibrosis: a historical timeline 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 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 campregulated chloride channel by complementation studies. 6

7 Classes of cystic fibrosis causing mutations Class 3: regulatory mutants that fail to respond normally to activation signals, e.g., G551D ADP ADP ATP PKA ATP ATP ADP Endosome Class 4: CFTR mutants that have altered channel properties, e.g., R117H Class 1: premature termination of CFTR mrna translation, e.g., S489X Golgi Nucleus ER Class 2: CFTR degradation in the endoplasmic reticulum, e.g., F508 Class 5: decreased functional CFTR synthesis or transport, e.g., A455E 7

8 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) unaffected 50% (wt, 9T, and mutant CFTR) vas deferens sweat duct airway pancreas 10% (wt protein, 5T/5T) 5% (wt protein, 5T, and severe mutant) 4% (R117H, 5T, and severe mutant) 1% (R117H, 5T, and severe mutant) <1% (G551D, F508) Pathogenesis of lung disease in cystic fibrosis Davis PB, et al. J Respir Crit Care Med. 1996;154:1229. Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Bronchial obstruction Infection Inflammation Bronchiectasis 8

9 Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Decrease mucus viscosity Augment clearance Decrease bacterial load Reduce host response Replace damaged lungs Bronchial obstruction Infection Inflammation Bronchiectasis Chest physiotherapy Mucolytics (rhdnase) Hypertonic saline Antibiotics Macrolides Corticosteroids Ibuprofen Transplantation Cystic fibrosis: median survival age, inhaled mucolytics Median survival age (years) airway clearance anti Staphylococcus antibiotics anti Pseudomonas antibiotics Year Cystic Fibrosis Foundation Registry, inhaled antibiotics

10 Treatment of cystic fibrosis lung disease Defective CF gene Defective/deficient CFTR Block Na + uptake Increase Cl efflux Decrease mucus viscosity Augment clearance Decrease bacterial load Reduce host response Replace damaged lungs Abnormal airway surface milieu Bronchial obstruction Infection Inflammation Bronchiectasis Amiloride UTP/ATP Hypertonic saline Mucolytics (rhdnase) Chest physiotherapy Antibiotics Macrolides Corticosteroids Ibuprofen Transplantation Cystic fibrosis: alternative therapies to effect bioelectric properties of the respiratory epithelium CF Altering other channels Na + Cl Cl Na + ENaC CFTR ClCa Cl Amiloride UTP/ATP Hypertonic saline 10

11 Treatment of cystic fibrosis lung disease Defective CF gene Increase CFTR protein Activate mutant form Block Na + uptake Increase Cl efflux Decrease mucus viscosity Augment clearance Decrease bacterial load Reduce host response Replace damaged lungs Defective/deficient CFTR Abnormal airway surface milieu Bronchial obstruction Infection Inflammation Bronchiectasis VX809 VX770 PTC124 Amiloride UTP/ATP Hypertonic saline Mucolytics (rhdnase) Chest physiotherapy Antibiotics Macrolides Corticosteroids Ibuprofen Transplantation Gentamicin induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations Wilschanski M. N Engl J Med. 2003; 349:1433. Response of nasal PD to chloridefree isoproterinol (mv) 8 6 p = Gentamicin concentration (%) pre treatment post treatment 11

12 Cystic fibrosis: correcting CFTR dysfunction Zeitlin P. N Engl J Med. 2004;351:606 G551D CFTR F508 CFTR Cell membrane VX770 Cell membrane Golgi Endosome apical trafficking degradation Proteasome Endosome Golgi ER post translational folding translation transcription Low temperature Glycerol ER VX809 Nucleus Nucleus 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 [Sweat chloride] (mmol/l) placebo VX770, 150 mg VX770, 250 mg days 12

13 Treatment of cystic fibrosis lung disease Provide normal gene Increase CFTR protein Activate mutant form Block Na + uptake Increase Cl efflux Decrease mucus viscosity Augment clearance Decrease bacterial load Reduce host response Replace damaged lungs Defective CF gene Defective/deficient CFTR Abnormal airway surface milieu Bronchial obstruction Infection Inflammation Bronchiectasis Gene therapy VX809 VX770 PTC124 Amiloride UTP/ATP Mucolytics (rhdnase) Chest physiotherapy Hypertonic saline Antibiotics Macrolides Corticosteroids Ibuprofen Transplantation 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) Ornithine transcarbamylase 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) Junctional epidermolysis bullosa (1) Neuronal ceroid lipofuscinosis (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) 13

14 Heartland Collaborative Annual Meeting, Friday, October 5, 2012 Cystic fibrosis: hitting the target Conclusions Children with cystic fibrosis are being identified much earlier. The diagnosis of cystic fibrosis is based on newborn screening, clinical features, and abnormal sweat chloride concentrations Airway clearance techniques, inhaled mucolytic agents, antibiotics and pancreatic enzyme replacement therapy are still the cornerstones of cystic fibrosis care. Newer mutation specific therapies are changing the disease trajectory for some patients. Treatment options for patients with cystic fibrosis will be increasingly defined by the patient s mutant CFTR alleles. 14