*27 Cystic Fibrosis and Bronchiectasis

Question 1

Bronchiectasis

• General
• An important cause of…
• Results from…
• Characterized clinically by…
• May be…
• Diseases characterized by bronchiectasis

Answer 1

• General
  
  • The abnormal and irreversible dilatation of the bronchi
  • A characteristic feature of a number of lung diseases
  • Less common than asthma and COPD due to tobacco use
• An important cause of airway obstruction
• Results from chronic airway infection and/or inflammation
• Characterized clinically by cough, sputum production, and varying degrees of dyspnea
• May be…
  
  • Localized, as in prior infection or airway obstruction from a foreign body
  • Diffuse, as in disorders of airway defense mechanisms and a variety of other causes
• Diseases characterized by bronchiectasis
  
  • Immotile cilia syndrome
  • Cystic Fibrosis (CF)

Question 2

Airway host defense and the pathogenesis of bronchiectasis

• In the normal individual, infection of the conducting airway occurs when…
• The airway epithelium
  
  • Consists of…
  • In the proximal airway (bronchus),…
  • In the distal airway (bronchiole),…
  • In both bronchi and bronchioles,…

Answer 2

• In the normal individual, infection of the conducting airway occurs when…
  
  • Pathogens gain access to the lower airway and overcome or circumvent the innate host defense mechanisms that prevent infection
• The airway epithelium
  
  • Consists of a number of specialized cell types whose secretory products play an important role in airway function
  • In the proximal airway (bronchus), the ciliated cell and goblet cell appear critical
  • In the distal airway (bronchiole), the ciliated cell and clara cell are particularly important for airway homeostasis and host defense
  • In both bronchi and bronchioles, normal regulation of ion transport (as revealed by CF) and mucociliary clearance (as revealed by immotile cilia syndromes) is critical to the innate response against infection

Question 3

Airway host defense and the pathogenesis of bronchiectasis:
Innate defense mechanisms in the lung + their physiological effect or examples

• Secreted proteins with anti-microbial activity
• Mucus blanket (gel layer)
• Airway surface liquid beneath mucus blanket (sol layer)
• Synchronous ciliary activity
• Alveolar macrophages

Answer 3

• Secreted proteins with anti-microbial activity
  
  • Lactoferrin, lysozyme, anti-microbial peptides (defensins and cathelecidins), collectins, secretory IgA
• Mucus blanket (gel layer)
  
  • Contains mucins that bind pathogens and allows for clearance via mucociliary escalator
• Airway surface liquid beneath mucus blanket (sol layer)
  
  • Reservoir for anti-microbial proteins and fluid layer that allows for normal mucociliary clearance
• Synchronous ciliary activity
  
  • Clears mucus blanket with bound pathogens
• Alveolar macrophages
  
  • Resident phagocytic cells in the airspace

Question 4

Airway host defense and the pathogenesis of bronchiectasis

• If pathogens overcome the innate airway host defense, an adaptive immune response ensues that includes…
• Normally,…
• In contrast, the final common pathway in the development of bronchiectasis is…
• This leads to…
• The latter create protease imbalance such that…

Answer 4

• If pathogens overcome the innate airway host defense, an adaptive immune response ensues that includes…
  
  • (a) recruitment of inflammatory cells that have intrinsic anti-microbial properties,
  • (b) secretion of mucus and fluid that promotes clearance of airway pathogens and inflammatory cells, and
  • (c) an increase in ciliary beat frequency that promotes mucociliary clearance.
• Normally,…
  
  • The airway effectively clears viral or bacterial infection
  • The inflammatory response resolves
  • Airway function reverts to normal
• In contrast, the final common pathway in the development of bronchiectasis is…
  
  • Inflammation that does not resolve
• This leads to…
  
  • Airway obstruction with mucus
  • Inflammatory cells
  • Leukocyte products
• The latter create protease imbalance such that…
  
  • The normal anti-protease activity in the lung is overcome
  • The airway wall remodels
  • Ultimately leads to distortion of airway architecture
  • In the case of bronchiectasis, the airways become floppy and dilated

Question 5

Airway host defense and the pathogenesis of bronchiectasis

• Historically, bronchiectasis most commonly resulted from…
• In some individuals who become infected with these organisms, infection leads to…
• The decline in the incidence of bronchiectasis in the post-antibiotic era attests to the importance of…
• Airway obstruction in bronchiectasis results from…
• As the disease progresses,…

Answer 5

• Historically, bronchiectasis most commonly resulted from…
  
  • Acute necrotizing infections such as pertussis (whooping cough), Staphyloccus aureus, or Mycobacterium tuberculosis
• In some individuals who become infected with these organisms, infection leads to…
  
  • Acute inflammation
  • Destruction of the muscle, cartilage, and fibrous tissue of the airway wall
  • Airway dilatation (bronchiectasis)
• The decline in the incidence of bronchiectasis in the post-antibiotic era attests to the importance of…
  
  • Infection in the pathogenesis of bronchiectasis
• Airway obstruction in bronchiectasis results from…
  
  • Plugging of the airways with mucus and inflammatory cells
• As the disease progresses,…
  
  • Disruption of the normal bronchial cartilage from chronic inflammation allows expiratory collapse of the airway wall
  • Thus, both plugging and airway collapse contribute to the development of obstructive lung disease in patients with bronchiectasis

Question 6

Airway host defense and the pathogenesis of bronchiectasis

• In other conditions, such as peanut aspiration,…
• In contrast, in diseases such as immotile cilia syndrome, cystic fibrosis, and immunoglobulin deficiency,…

Answer 6

• In other conditions, such as peanut aspiration,…
  
  • Chronic inflammation develops in the absence of infection
  • Weeks, months, or years after the initial, oftentimes localized segment of inflammation, chronic bacterial infection develops in the airways damaged by the initial inflammatory insult
• In contrast, in diseases such as immotile cilia syndrome, cystic fibrosis, and immunoglobulin deficiency,…
  
  • Innate anti-microbial function in the airway is impaired
  • Results in more diffuse acute and chronic airway infection, with attendant inflammation, protease excess, partial destruction of the airway wall, and ultimately, airway dilatation (bronchiectasis)
  • As occurs occasionally with remote infections, structural damage to the airway wall further impairs defense against infection, predisposing to recurrent or chronic infection, and establishing a vicious cycle

Question 7

Causes of bronchiectasis

• Acute bronchopulmonary infection
  
  • Childhood diseases
  • Infections
• Bronchial obstruction
  
  • Foreign body aspiration
  • Neoplasms
  • Chronic obstructive lung disease
  • Adenopathy
• Disorders of airway defense against infection
  
  • Ciliary abnormalities
  • Defects in airway surface fluid
  • Immunodeficiencies
• Congenital or acquired anatomic defects
• Miscellaneous disorders
  
  • Irritant inhalation
  • Chronic lung transplant rejection
  • Allergic response to fungal antigens

Answer 7

• Acute bronchopulmonary infection
  
  • Childhood diseases
    
    • Pertussis, measles
  • Infections
    
    • Staphylococcus aureus, Klebsiella, Hemophilus, Mycobacterium tuberculosis, Histoplasmosis
• Bronchial obstruction
  
  • Foreign body aspiration
    
    • Chicken bone, peanut, or legume aspiration
  • Neoplasms
    
    • Bronchial adenoma or carcinoma
  • Chronic obstructive lung disease
    
    • Alpha-1-anti-trypsin deficiency
  • Adenopathy
    
    • Tuberculosis, sarcoidosis
• Disorders of airway defense against infection
  
  • Ciliary abnormalities
    
    • Primary ciliary dyskinesia/Immotile cilia syndrome with or without Kartagener’s (situs inversus)
  • Defects in airway surface fluid
    
    • Cystic fibrosis
  • Immunodeficiencies
    
    • Congenital or acquired IgG or IgG subclass deficiency, IgA deficiency, Chronic granulomatous disease
• Congenital or acquired anatomic defects
  
  • Cartilage deficiency (Campbell- Williams syndrome), relapsing polychondritis, bronchomalacia, amyloidosis, pulmonary sequestration
• Miscellaneous disorders
  
  • Irritant inhalation
    
    • Examples - ammonia, talc, smoke, detergents
  • Chronic lung transplant rejection
    
    • Obliterative bronchiolitis
  • Allergic response to fungal antigens
    
    • Allergic bronchopulmonary aspergillosis (ABPA)

Question 8

Pathogenesis of cystic fibrosis

• The pathogenesis of Cystic Fibrosis (CF) has been more extensively studied than the other disorders in large part because…
• CF
• Genetic basis for CF

Answer 8

• The pathogenesis of Cystic Fibrosis (CF) has been more extensively studied than the other disorders in large part because…
  
  • CF is the most common life-shortening inherited disease among Caucasians
• CF
  
  • Autosomal recessive disease involving one or more epithelial organ
  • Have abnormally salty sweat
  • Have abnormal chloride transport in the sweat duct and airway epithelium
• Genetic basis for CF
  
  • Positional cloning to mutations in an epithelial chloride channel, the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Question 9

Pathogenesis of cystic fibrosis:
Mutation classes

• Normal transcription and translation of the CF gene results in…
• Class I CF mutations
• Class II CF mutations
• Class III and IV mutations
• Class V mutations
• While correlation between genotype and clinical manifestations (phenotype) has been difficult to demonstrate for CF, a number of mutations have been correlated with a more mild phenotype that often…
• Other mutations have been predictive of…

Answer 9

• Normal transcription and translation of the CF gene results in…
  
  • A protein that is processed in the biosynthetic pathway and transported to the apical membrane where it serves as a chloride and bicarbonate channel and ion conductance regulator
• Class I CF mutations
  
  • A premature ‘stop’ mutation precludes production of a fulllength protein
• Class II CF mutations
  
  • Include the most common mutation – deletion of phenylalanine at position 508 (F508del)
  • Accounts for over 70% of CF mutations- the mutant CFTR protein misfolds
  • Targeted for proteolytic degradation in the biosynthetic pathway
• Class III and IV mutations
  
  • A full-length CFTR protein traffics to the cell membrane but is defective in channel regulation or conductance
• Class V mutations
  
  • Reduced mRNA and protein production such that there is a relative deficiency of CFTR at the cell surface
• While correlation between genotype and clinical manifestations (phenotype) has been difficult to demonstrate for CF, a number of mutations have been correlated with a more mild phenotype that often…
  
  • Does not lead to characteristic clinical manifestations until adulthood
• Other mutations have been predictive of…
  
  • Normal pancreatic function

Question 10

Pathogenesis of cystic fibrosis

• Molecular basis for fluid transport in the airway
• In normal airways, there is a finely regulated balance between…
• Sodium absorption is regulated primarily by…
• CFTR
• In CF, the gene encoding for the CFTR chloride channel…

Answer 10

• Molecular basis for fluid transport in the airway
  
  • Critical importance of chloride conductance for normal airway homeostasis
• In normal airways, there is a finely regulated balance between…
  
  • Ion absorption and secretion that maintains an appropriate volume and pH of airway surface liquid to allow for normal ciliary and mucus movement
• Sodium absorption is regulated primarily by…
  
  • An amiloride-sensitive sodium channel (ENaC)
• CFTR
  
  • An ion channel that appears to regulate the activity of other apical membrane and intracellular ion channels in epithelial cells
  • Down-regulates activity of ENaC
  • A chloride and bicarbonate channel whose activity is regulated by cAMP and ATP
• In CF, the gene encoding for the CFTR chloride channel…
  
  • Is mutated, resulting in abnormal expression or function of the CFTR chloride channel

Question 11

Pathogenesis of cystic fibrosis

• CF airway epithelia
• The critical importance of sodium hyperabsorption in the pathogenesis of CF
• CFTR
  
  • Expressed in…
  • Regulates…
• Mutations in the CF gene…
  
  • Impair…
  • Lead to…

Answer 11

• CF airway epithelia
  
  • Lack a cAMP-mediated chloride secretory response
  • Excessive activity of the epithelial sodium channel ENaC, resulting in excess sodium absorption
• The critical importance of sodium hyperabsorption in the pathogenesis of CF
  
  • Over-expression of one subunit of ENaC led to the manifestations of CF
    
    • Mucus obstruction of small airways
    • Predisposition to bacterial infection
    • Inflammation
  • The net effect of the CFTR and ENaC perturbations
    
    • The airway surface liquid in CF lacks sufficient volume for normal mucociliary clearance
• CFTR
  
  • Expressed in both surface epithelium and submucosal glands in the proximal airway
  • Regulates the volume of the airway surface fluid
• Mutations in the CF gene…
  
  • Impair airway fluid homeostasis
  • Lead to reduced mucociliary clearance

Question 12

Pathogenesis of cystic fibrosis

• Another potential mechanism whereby CF mutations lead to infection is by affecting the intracellular processing of glycoconjugates
• In other epithelial organs affected in CF, the CFTR channel appears to affect other ion transport processes
  
  • In the sweat gland, the CFTR channel is necessary for…
  • In CF, the mutated CFTR channel…
  • Diagnostic test for CF

Answer 12

• Another potential mechanism whereby CF mutations lead to infection is by affecting the intracellular processing of glycoconjugates
  
  • Leads to abnormal surface glycolipids that contribute to bacterial adhesion
  • Leads to abnormally glycosylated mucins that contribute to reduced mucociliary clearance
• In other epithelial organs affected in CF, the CFTR channel appears to affect other ion transport processes
  
  • In the sweat gland, the CFTR channel is necessary for…
    
    • Sodium chloride transport from the sweat duct lumen into the interstitium for production of the normally hypotonic sweat (Na and Cl concentrations < 40 mEq/L)
  • In CF, the mutated CFTR channel…
    
    • Limits Na Cl absorption in the sweat duct, leading to the elaboration of an excessively salty sweat (Na and Cl concentrations > 60 mEq/L)
  • Diagnostic test for CF
    
    • Sweat test

Question 13

Pathogenesis of cystic fibrosis

• In the pancreas
  
  • CFTR is primarily responsible for…
  • In CF, the mutated CFTR channel…
• In the vas deferens, CFTR appears necessary for…

Answer 13

• In the pancreas
  
  • CFTR is primarily responsible for…
    
    • Bicarbonate secretion and the production of alkaline pancreatic secretions
    • Maintaining thin pancreatic secretions
    • Limiting the activity of proteases such as amylase and lipase until contact with acidic gastric juices in the duodenum
  • In CF, the mutated CFTR channel…
    
    • Precludes bicarbonate secretion
    • Leads to mucus inspissation in the pancreatic ducts and proteolysis
    • Eventuates in pancreatic fibrosis and/or recurrent episodes of pancreatitis
• In the vas deferens, CFTR appears necessary for…
  
  • Patency and development
  • Most men with CF have congenital bilateral absence of the vas deferens (CBAVD), and male infertility

Question 14

Symptoms and signs of bronchiectasis

• The major historical clues to the presence of bronchiectasis
• Associated symptoms
• Other associated problems

Answer 14

• The major historical clues to the presence of bronchiectasis
  
  • Cough
    
    • ​Often chronic or recurrent
    • May vary in severity over time
  • Chronic sputum production
    
    • Typically purulent (green or yellow, occasionally foul smelling)
    • Often worse in the morning
    • Usually voluminous
• Associated symptoms
  
  • Pleuritic chest pain
  • Wheezing or chest tightness
  • Blood streaking of the sputum
  • Frank bleeding (hemoptysis)
• Other associated problems
  
  • Chronic or recurrent acute sinus infection
    
    • Particularly in CF, primary ciliary dyskinesia, and immunoglobulin deficiencies
  • Malabsorption due to pancreatic insufficiency or male infertility (CF)
  • A history of childhood or recurrent “pneumonia”
  • A family history of CF or chronic lung disease
  • A history of difficult to control asthma

Question 15

Symptoms and signs of bronchiectasis:
Physical findings that should raise suspicion for bronchiectasis and help differentiate bronchiectasis from other more common obstructive lung diseases, such as asthma and chronic lung disease associated with tobacco use

Answer 15

• Clubbing of the digits
  
  • Occurs often in bronchiectasis, but rarely in patients with asthma or COPD
• Nasal polyps and evidence for nasal inflammation (secretions)
  
  • May occur in asthma, but should place bronchiectasis in the differential diagnosis
• Mid-inspiratory crackles,
  
  • Crackles that are most apparent in early and mid inspiration
  • Highly suggestive of bronchiectasis
  • Contrast with the late inspiratory crackles seen with pulmonary edema, pulmonary fibrosis, or other causes of alveolar fluid accumulation

Question 16

Radiographic findings of bronchiectasis

• Typical radiographic findings of bronchiectasis and their causes
• Findings on plain chest x-ray exam
• Computerized Tomography (CT scanning) with high resolution (~1 mm slices)

Answer 16

• Typical radiographic findings of bronchiectasis and their causes
  
  • Often the first clue to the presence of bronchiectasis in a patient with chronic cough or obstructive lung disease
• Findings on plain chest x-ray exam
  
  • May be non-specific
  • The plain chest x-ray should therefore not be used exclusively to rule out bronchiectasis
• Computerized Tomography (CT scanning) with high resolution (~1 mm slices)
  
  • The current procedure of choice for the detection of bronchiectasis
  • Has replaced bronchography, in which contrast material is instilled to the airway prior to conventional radiography

Question 17

Radiographic findings

• Chest x-ray findings
• CT findings

Answer 17

• Chest x-ray findings
  
  • Linear radiolucencies or “interstitial pattern”
  • Parallel markings radiating from the hilum (tram lines), or ring shadows
  • Thick lines radiating from the hilum (toothpaste lines), or nodular densities
  • Cysts, with or without fluid levels
  • Peri-bronchial haziness
  • Atelectasis (collapse from airway plugging)
  • Consolidation/pneumonia
  • Hyperinflation with diaphragm flattening and increased retrosternal airspace
• CT findings
  
  • Dilatation and thickening of the conducting airways
  • Tree and bud appearance to distal airway
  • Nodular opacities representing dilated airways filled with mucus
  • Thick walled cysts, with or without fluid levels

Question 18

Pulmonary function tests

• Pulmonary function abnormalities in bronchiectasis
• In early disease, the PFTs may be…
• Forced Expiratory Flow at 25-75% of the FVC (the FEF25-75)
• Functional Residual Capacity (FRC)
• FEV1 and FEV1/FVC
• Diffusion capacity
• In the end stages of diffuse bronchiectasis

Answer 18

• Pulmonary function abnormalities in bronchiectasis
  
  • Non-specific
  • Do not differentiate bronchiectasis from other obstructive lung diseases
• In early disease, the PFTs may be…
  
  • Normal, particularly in localized bronchiectasis
• Forced Expiratory Flow at 25-75% of the FVC (the FEF25-75)
  
  • The earliest abnormality
  • A reduction in expiratory flow rates reflects obstruction of the smaller conducting airways
• Functional Residual Capacity (FRC)
  
  • Elevations of the FRC reflect the hyperinflation that occurs with airway obstruction, and may occur early in the disease process
• FEV1 and FEV1/FVC
  
  • Over time, the FEV1 and FEV1/FVC ratio decrease
• Diffusion capacity
  
  • Generally preserved until late in the disease
  • May be accompanied by increases in the alveolar-arterial oxygen gradient
• In the end stages of diffuse bronchiectasis
  
  • Chronic respiratory failure develops, with hypoxemia and hypercapnea due to the ventilation-perfusion abnormalities and increased dead space ventilation that accompany severe airway obstruction

Question 19

Diagnostic findings in specific causes of bronchiectasis

• Cystic fibrosis
• Primary ciliary dyskinesia / immotile cilia syndrome
• Immunodeficiency state
• Foreign body or bronchial obstruction
• Allergic bronchopulmonary aspergillosis
• Alpha-1 antitrypsin deficienc

Answer 19

• Cystic fibrosis
  
  • Sweat chloride > 60 mEq/L on two separate occasions; identification of two CF gene mutations; lack of chloride secretion on nasal potential difference measurement
• Primary ciliary dyskinesia / immotile cilia syndrome
  
  • Nasal mucociliary clearance of saccharin severely decreased; abnormal ciliary beat frequency in nasal epithelial cells in vitro; lack of dynein arms on ciliary microtubules of nasal epithelial cells by electron microscopy; abnormal radionuclide mucus clearance scan
• Immunodeficiency state
  
  • Decreased IgA, IgG, or IgG subclass (especially IgG2 or IgG4)
• Foreign body or bronchial obstruction
  
  • Identification by CT scan or bronchoscopy
• Allergic bronchopulmonary aspergillosis
  
  • Elevated IgE, IgE specific antibodies against aspergillus antigens, skin test reactivity against aspergillus
• Alpha-1 antitrypsin deficiency
  
  • Reduced serum level of alpha-1 antitrypsin; alpha-1 phenotype/genotype testing

Question 20

Management of bronchiectasis

• Abnormal CFTR
• Decreased Cl- secretion and increased Na+ absorption
• Airway obstruction
• Infection
• Inflammation
• Airway destruction

Answer 20

• Abnormal CFTR
  
  • Gene therapy
  • CFTR correctors and potentiators
• Decreased Cl- secretion and increased Na+ absorption
  
  • ion channel modulators
• Airway obstruction
  
  • Airway clearance and hypertonic agents
• Infection
  
  • Antibiotics: systemic / inhaled
• Inflammation
  
  • Steroids and other anti-inflammatories
• Airway destruction
  
  • Lung transplant

Question 21

Therapeutic options for bronchiectasis

• Airway hygiene
• Bronchodilators
• Antibiotics

Answer 21

• Airway hygiene
  
  • Reduce the mucus obstruction that occurs in bronchiectasis by…
    
    • Chest Physical Therapy (CPT) and Postural Drainage
    • Resistance to expiratory airflow (Flutter or Accapella device, Positive Expiratory Pressure (PEP) valve)
    • Chest wall oscillation (chest wall oscillator – Chest Vest)
• Bronchodilators
  
  • Airway inflammation is often accompanied by airway hyper-reactivity
  • Bronchodilators such as beta2-agonists (albuterol and others) or the quartarnary amine ipratropium (atrovent) are often used to minimize airway obstruction
  • Beta-agonists increase ciliary beat frequency, thereby promoting mucociliary clearance
• Antibiotics
  
  • Systemic or aerosolized antibiotics are useful for management of acute infectious exacerbations of bronchiectasis
  • Intermittent courses of oral antibiotics are often used effectively
  • Irrespective of the etiology of bronchiectasis, many patients ultimately become infected with Pseudomonas aeruginosa, which creates a “biofilm” that prevents its eradication
  • Aerosolized antibiotics, such as tobramycin (TOBI) and aztreonam (Cayston) reduce the density of Pseudomonas in airway secretions, and appear to slow the progression of obstructive airway disease in Cystic Fibrosis

Question 22

Therapeutic options for bronchiectasis

• Mucolytics
• Vaccination
• Support for chronic respiratory failure
• Pulmonary transplantation

Answer 22

• Mucolytics
  
  • Recombinant human DNase has been shown to reduce mucus viscosity and promote mucociliary clearance in Cystic Fibrosis, but has not proven effective in other diseases associated with bronchiectasis
  • Other approaches to increasing mucus clearance are hypertonic saline and other osmotically active agents, such as mannitol, that increase the volume of airway surface liquid to promote mucociliary clearance
• Vaccination
  
  • Patients with chronic obstructive lung diseases are at increased risk for complications of influenza and should receive yearly flu vaccination
  • Vaccination against pneumococcus should also be given
• Support for chronic respiratory failure
  
  • Oxygen and non-invasive mechanical ventilation (Bi-level Positive Airway Pressure – BiPAP) are useful for treating late stage disease
• Pulmonary transplantation
  
  • Bilateral lung transplant has been performed successfully in patients with CF, immotile cilia syndrome, and post-infectious bronchiectasis
  • One year survival rates of ~85% and five year survival of ~60%

Question 23

Future therapies for CF:
Progress towards personalized medicine

• Gene and cell based therapies
• Understanding ion transport regulation in CF appears likely to identify drugs that may be useful for…

Answer 23

• Gene and cell based therapies
  
  • Delivery of a normal copy of the CF gene to epithelial cells in the lung and other organs via gene therapy
  • Gene editing with oligonucleotides
  • Stem cell therapy in which stem cells are modified ex vivo to correct the CF defect
  • A significant number of technological hurdles must be overcome for these approaches to be successful
• Understanding ion transport regulation in CF appears likely to identify drugs that may be useful for…
  
  • Mucus clearance in bronchiectasis and other obstructive lung diseases that are not due to CF mutations

Question 24

Future therapies for CF:
Progress towards personalized medicine

• Modulation of the CFTR protein or other ion channels
• The best example of this
• Ivacaftor
• Other compounds
• Personalized medicine

Answer 24

• Modulation of the CFTR protein or other ion channels
  
  • To partially or fully restore normal ion channel function
  • Correct the physiological abnormalities in fluid homeostasis in the airway and pancreas
• The best example of this
  
  • High through put drug screening to identify drugs that correct CFTR gating or processing in the biosynthetic pathway
• Ivacaftor
  
  • Targeted at a specific CF gene mutation, G551D, a Class III CF gating mutation characterized by defective channel regulation
  • Restores chloride conductance to cells expressing a G551D CFTR mutation
  • Developed into an oral medication that partially corrects CFTR function in the sweat gland, GI tract, and respiratory system
  • Beneficial as monotherapy for up to 15% of patients with CF
• Other compounds
  
  • Correct the common F508del mutation
  • Provide a new therapy for the majority of patients with CF are in various stages of clinical studies
• Personalized medicine
  
  • Knowing the genetic mutation will guide the choice of drug therapies to correct the physiological abnormality at the cell and organ level and thereby prevent or slow progression of disease