Lecture 12 - Current and Future CF Therapies

Question 1

What is a CF centre of excellence?

Answer 1

A centre with over 50 CF patients

Question 2

Physiotherapy techniques for CF
1)
2)
3)
4)
5)

Answer 2

1) Gravity assisted drainage
2) Active cycle of breathing techniques
3) Autogenic drainage
4) Positive expiratory pressure
5) Activity, exercise

Question 3

Two uses for antimicrobials in CF

Answer 3

Prophylactic, for exacerbations

Question 4

What is the procedure for treating a severe infection in CF?

Answer 4

Take patient to hospital, put them on IV antibiotics for a few weeks

‘Tune up’

Question 5

Advantage of nebulised antimicrobials

Answer 5

Can be targeted directly to LRT

Lower dose can be used –> Reduced side effects

Question 6

Ways to susceptibility test patient microbes

Answer 6

Sputum test

Question 7

How can resistance be avoided in CF patients?

Answer 7

Always give at least 2 different antibiotics

Question 8

Difficulties in treating CF patients with antibiotics
1)
2)
3)

Answer 8

1) Side effects, especially from long-term use
2) Antibiotic resistance in bacteria
3) CF patients have different pharmacokinetics. Often need much higher doses, EG: aminoglycosides

Question 9

Bacteria which can be spread between CF patients
1)
2)
3)

Answer 9

1) Pseudomonas
2) Burkholderia cepacia
3) MRSA

Question 10

Way to reduce disease spread in hospitalised CF patients

Answer 10

Patient segregation - Don’t allow 2 CF patients to interact

Question 11

Mucolytics
1)
2)
3)

Answer 11

1) Recombinant human deoxyribonuclease-1 (pulmozyme)
2) Hypertonic saline
3) Mannitol

Question 12

Effect of mannitol

Answer 12

Osmotic agent

Draws water into airway surface liqud

Question 13

Anti-inflammatory agents for CF
1)
2)
3)

Answer 13

1) Azithromycin
2) Glucocorticosteroids
3) NSAID - Ibuprofen

Question 14

Issues with glucocorticosteroids and NSAID therapies

Answer 14

Many side-effects

EG: NSAIDs are nephrotoxic for long-term use

Question 15

Energy requirements of CF patients

Answer 15

120-150% of normal

Question 16

Proportion of CF diet that is fat

Answer 16

35-40%

Question 17

Pancreatic enzyme tablet

Answer 17

Creon

Question 18

When is creon taken?

Answer 18

With all foods containing fat, protein or complex carbohydrates

Question 19

Creon dose

Answer 19

500-2000 units of lipase/kg body weight/meal

Question 20

What is most CF antibiotic research focussed on?

Answer 20

Novel delivery systems

Can direct delivery of antibiotics can reduce side effects, increase microbicidal activity

Question 21

Sildenafil

Answer 21

Viagra

Question 22

Potential uses for sildenafil

Answer 22

Antiinflammation, treat chronic hypertension

Question 23

Novel antibiotic delivery mechanisms
1)
2)

Answer 23

1) Dry powder inhaler

2) Nebulised

Question 24

Future anti-inflammatory therapies for CF
1)
2)
3)
4)

Answer 24

1) Glutathione
2) Sildenafil
3) KB001A
4) Alpha-1 antitrypsin

Question 25

Glutathione therapy

Answer 25

Replaces glutathione, an important antioxidant

Question 26

What is sildenafil?

Answer 26

Phosphodiesterase inhibitor

Question 27

What is KB001?

Answer 27

A humanised monoclonal Fab fragment

Targets Pseudomonas virulence factor, reduces local inflammation

Question 28

What is alpha-1 antitrypsin?

Answer 28

An antiprotease

Can help resist overwhelming of antiproteases by neutrophil response

Question 29

Problems with gene therapy
1)
2)
3)

Answer 29

1) Lungs are still an effective barrier to foreign bodies
2) Viral vectors have caused deaths of some testing volunteers
3) Unmethylated CpG DNA on plasmid, which can cause mild flu-like symptoms

Question 30

Non-viral gene therapy vectors

Answer 30

Cationic liposomes complexed with plasmid DNA expressing CFTR

Question 31

Outcome of gene therapy trials
1)
2)
3)

Answer 31

1) Proof of concenpt
2) Most only stage I and II trials
3) Over 30 trials to date

Question 32

Problems with possible stem-cell therapy
1)
2)

Answer 32

1) Under 1% frequency of engraftment in lungs

2) Almost always causes severe lung damage

Question 33

Example of a successful protein rescue therapy

Answer 33

Ivacaftor

Question 34

Ivacaftor

Answer 34

Potentiator protein
Keeps defective class III mutation CFTR channel open
Corrects G551D mutation

Question 35

Positive aspects of Ivacaftor
1)
2)
3)

Answer 35

1) Significant improvement in lung function
2) Significant weight increase
3) Significant decrease in symptoms

Question 36

Proof that ivacaftor corrects underlying defect of type III CF

Answer 36

Chloride sweat values are normal

Question 37

Ivacaftor dosage

Answer 37

150mg tablet, twice daily

Question 38

Drawbacks of ivacaftor
1)
2)

Answer 38

1) $294,000 per patient per year

2) G551D affects 4% of patients worldwide

Question 39

What is lumacaftor?

Answer 39

A corrector, which is used to treat type II mutations

Increases F508del CFTR trafficked to cell surface

Question 40

Reason for combining lumacaftor and ivacaftor

Answer 40

Once type II proteins trafficked to surface, don’t function properly

Question 41

Efficacy of lumacaftor

Answer 41

CFTR transport 15% of wild type

Question 42

Efficacy of lumacaftor combined with ivacaftor

Answer 42

CFTR transport 30% of wild type

Question 43

Ataluren

Answer 43

A small molecule compound, promotes read-through of premature stop codons (type I mutation)