Therapeutic Strategies for Cystic Fibrosis from University of Portsmouth

Learning Objectives for Cystic Fibrosis Therapeutic Approaches

On completion of this session you should be able to

1. Understand the rationale behind CF therapeutic approaches
2. Describe current treatment strategies for CF
3. Explore CFTR modulator therapies

For the last 70 years treatment has aimed to reduce obstruction and infection of the airways. O Airway obstruction can be reduced using chest physiotherapy, bronchodilators and agents that alter the tenacious properties of CF sputum (mucolytics). Pseudomonas aeruginosa is a gram-negative organism and typical antibiotic therapy would include inhaled colomycin (a polymyxin) with other oral or intravenous antibiotics. More recently the aminoglycoside tobramycin has been developed for inhaled use. The early and aggressive use of antibiotics has been shown to significantly improve FEV1. More recently anti-inflammatory therapy has been introduced. More definitive therapies aimed at the basic defect, including manipulation of ion transport, activation of mutant CFTR and gene therapy are now on the horizon. Since 1985, lung transplantation has become an option for patients with end-stage lung disease, when FEV1 less than 30% predicted. Double-lung transplants in adults and heart- lung transplants in children result in about 67% survival at 1 year. This falls to 33% at 8 years. The lack of suitable donors and long waiting lists has led to living donor options, with similar or better survival rates.

Treatment of Lung Disease in Cystic Fibrosis

• Reducing airway obstruction
  • chest physiotherapy
  • bronchodilators
  • mucolytics
• Controlling infection
  • antibiotics
• Controlling inflammation
  • corticosteroids
  • NSAIDS
  • anti-proteases
• Correcting the basic defect
  • gene therapy
  • activation of mutant CFTR
  • manipulation of ion transport
• Lung transplantation
  • lung cadaver donor
  • heart-lung
  • bi-lobar, living donor

Understanding Mucus in Cystic Fibrosis

. Normally - nothing! EXCESSIVE MUCUS: · Reduces airflow · Invites infection · Restricts the delivery of other inhaled drugs, including gene therapy vectors. Mucus plays a vital role in our bodies, particularly in the respiratory system. It helps trap dust, bacteria, and other harmful particles, preventing them from reaching the lungs. So, under normal circumstances, there's absolutely nothing wrong with mucus! However, when mucus production becomes excessive, as seen in cystic fibrosis (CF) and other respiratory conditions, it leads to serious problems.

> Thick, sticky mucus can clog the airways, making it difficult for air to move in and out of the lungs. This leads to breathlessness, wheezing, and reduced lung function, worsening over time in CF patients. Excess mucus creates a perfect environment for bacteria to grow and persist, leading to chronic lung infections. In CF, patients often suffer from Pseudomonas aeruginosa and other opportunistic bacterial infections, which cause inflammation and lung damage. Inhaled medications, including bronchodilators, antibiotics, and gene therapy vectors, must penetrate the mucus to reach their targets. Excess mucus can block drug absorption, reducing the effectiveness of treatments in CF patients.

Chest Physiotherapy and Bronchodilators in CF

Clearing the airways of tenacious purulent secretions has been the cornerstone of CF therapy for more than 40 years. Traditional chest physiotherapy includes postural drainage and chest percussion and vibration, manually or with a mechanical percussor. Newer techniques and devices, such as the high frequency chest oscillation therapy vest, may produce superior results, ie the expectoration of larger volumes of sputum, and replace traditional therapy. The success of the different techniques depends on the age of the patient, the ability of children to master them, and whether or not disease is localised to a particular lobe or segment of the lung. Bronchodilators, usually beta-adrenergic agonists or cholinergic blockers, are often nebulised and inhaled prior to chest physiotherapy to dilate small airways and facilitate mucus clearance. In some individuals bronchodilators may be harmful, and there is a paradoxical decrease in pulmonary function after bronchodilator use. This may occur in patients with floppy airways who depend on smooth muscle tone to keep the airway open, and prevent expiratory collapse.

Chest percussion and postural drainage

Bonds in Inflamed Airway Sputum

Types of bonds occuring in sputum from inflamed airways; H 1 O-HO -NH3+ ... SO3 s s s s s TS 1. covalent disulphide bonds; link mucin glycoprotein chain's 5. physical entanglements between mucin macromolecules 6. extracellular actin; forms parallel network in infection 7. extracellular DNA; forms parallel network in infection / 3. hydrogen bonds; link oligosaccharide side chains 2. ionic bonds; positive and negative charges on mucins interact 4. Van der Waals forces; oligo- saccharide side chains interdigitate S s

Components and Viscosity of CF Sputum

The main components of CF sputum are the mucins (10-50 mg/ml) produced by mucus glands, as well as DNA (1-15 mg/ml) and actin (0.1-1 mg/ml) released from neutrophils dying by necrosis. These molecules are all high molecular weight polymers that contribute to sputum viscosity. Mucins consist of a protein core, heavily glycosylated with oligosaccharide side chains. The sugar residues account for more than 80% of the weight of the molecule. Disulphide bonds link glycoprotein subunits into macromolecular mucin molecules with molecular weights of the order of millions. When chromatin spills from the nucleus of necrotic neutrophils in the CF airways, the histones are degraded and highly negatively charged linear DNA is released. Actin is a filamentous protein that forms the cytoskeleton of neutrophils and is also relatively negatively charged. Physical entanglements, and interactions between charged groups on sugar and amino acid residues, as well as disulphide bonds in mucin molecules, and hydrogen-bonding between carbohydrate side chains, contribute to mucus viscoelasticity.

Mucolytics for Cystic Fibrosis

Mucolytics in Clinical Use

In the clinic; Mucolytics reduce viscosity by disrupting polymer networks in the secretions. Physical entanglements are disrupted mechanically by high frequency oscillation, while other types of bonds are targeted by biochemical or pharmacological agents. Classic mucolytics sever disulphide bonds and depolymerise mucins, while newer mucolytics degrade filaments of DNA (deoxyribonuclease/Pulmozyme). Hypertonic saline and aerosolised heparin breakdown ionic bonds and the relatively weak hydrogen bonds between carbohydrate side chains.

• Deoxyribonuclease; (DNase, Pulmozyme, Dornase alfa), depolymerises DNA
• Sulphydryl reagents; target -S-S- bonds between mucin molecules, eg dithiothreitol, N-acetyl cysteine (type 1)
• High frequency oscillation; to disrupt physical entanglements (types 4+5)
• Mannitol; hyperosmotic to rehydrate the airways
• Hypertonic saline

Mucolytics in Development

In development;

• Heparin, dextran sulphate; highly ionic, negatively charged, molecules that disrupt ionic and hydrogen bonds (types 2+3)

Pathogenicity of Microorganisms in CF Airway

Is a microorganism pathogenic? and therefore requires antimicrobial treatment) Antimicrobial treatment is needed when a microorganism is regarded as pathogenic in the CF airway. To determine if an organism is truly pathogenic it should be associated with an increase in symptoms, and decline in lung function, as indicated in the slide. It should be associated with;

• acute pulmonary exacerbations of symptoms production, cough)
• development of an antibody response
• increasing chest radiographic signs of infection or altered high resolution chest CT images destruction)
• rapid decline in lung function (eg. mucoid Pseudomonas)
• increased mortality (eg. Burkholderia cepacia)

Anti-pseudomonal Therapy for Cystic Fibrosis

Early Eradication of Pseudomonas Infection

Initial Pseudomonas infection is non-mucoid, ie there is no alginate production, and it is generally completely susceptible to pseudomonal-specific antibiotics. Therefore, it is possible to completely eradicate Pseudomonas infection with early intensive use of antibiotics, before chronic infection with macrocolonies of bacteria in hypoxic plaques makes it impossible to eradicate. Recommended antibiotic therapy includes; Ciprofloxacin-a quinolone, active against gram positive and gram negative bacteria, but particularly active against Pseudomonas. Colistin-a polymyxin antibiotic active against gram negative organisms including Pseudomonas, but not absorbed by mouth, and therefore given by inhalation. Tobramycin-an aminoglycoside active against many gram negative organisms including Pseudomonas. Not absorbed from the gut, therefore given by inhalation. Possible side effects of ototoxicity and nephrotoxicity.

1. Early eradication of infection;

Chronic Pseudomonas Infection Management

2. Chronic infection with mucoid Pseudomonas

• Chronic infection with Pseudomonas is much harder to treat with antibiotics. And it is recommended that mucolytics and chest physiotherapy be carried out before maintenance therapy with inhaled antibiotics every day.
• A combination of inhaled therapy to reach high local concentrations and intravenous therapy during exacerbation of symptoms is required. High doses of intravenous antibiotics are recommended because of the inaccessibility of Pseudomonas in mucus plugs. Patients with CF are treated with antibiotics every day of their lives, therefore careful monitoring for side effects is needed. Increasing resistance of Pseudomonas to inhaled tobramycin means that patients often cycle between different combinations of antibiotics to delay or avoid the development of resistance.
• Major problems for antibiotic therapy are B cepacia complex and S. maltophilia which are inherently multiresistant.
• Maintenance therapy with inhaled colistin or aminoglycosides to reach high airway concentrations
• Acute exacerbations require intravenous therapy - penicillin (ticarcillin, piperacillin), cephalosporins (ceftazidime), aminoglycosides, colistin.