Cystic Fibrosis

Question 1

What is cystic fibrosis and what does it cause?

Answer 1

It is an autosomal disease caused by a defective gene, which clogs the lungs & pancreas with thick sticky mucus

Question 2

What are the symptoms of cystic fibrosis?

Answer 2

1. Polyps - which narrow the nasal cavity
2. Coughing + sputum
3. Recurrent infections
4. Salty skin
5. Clubbing of hands
6. Pancreatic insufficiency

Question 3

Which defective gene is responsible for CF & on which chromosome is it located?

Answer 3

CFTR: cystic fibrosis transmembrane regulator

It is located on chromosome 7.

Question 4

What happens in the mutation of this CFTR protein and what does it lead to?

Answer 4

Transcription/translation of CFTR is altered, causing its protein folding to be incorrect.
This leads to abnormal Cl- channels from forming.

Question 5

Why does Na+ uptake increase in CF?

Answer 5

Because the Na+/Cl- exchanger is altered due to the defected CFTR gene, so Na+ is over absorbed by cells.

Question 6

What is the consequence of Na+ build up in CF?

Answer 6

Salty skin due to excess Na+ ions.

Mucus also becomes more sticky & begins to grow on membrane surfaces

Question 7

Why are people with CF more prone to infections?

Answer 7

Because the mucus provides a medium for bacteria to grow in.
Mucocillary clearance also fails, so mucus is not moved by cilia to the nose/lungs.

Question 8

Patients with CF also have a low airway surface liquid layer (ASLL). What occurs because of this?

Answer 8

1. Altered mucosal clearance
2. Clogged airways with mucus
3. Lung inflammation & damage

Question 9

What happens in the 6 functional classes of CF?

Answer 9

CLASS 1

• Mild CF
• No mRNA, protein or codon mutations

CLASS 2

• mRNA formed, some mutations but patient is stable
• Depletion of phenylalanine

CLASS 3

• no mRNA
• Impaired gating of protein channel
• Glycine replaced with aspartic acid

CLASS 4

• Decreased gene function due to mutations
• Impaired gating & passage of ions

CLASS 5

• Decreased protein formation
• No gating/passage of ions

CLASS 6

• Severe CF
• Mutations reduce quantity & quality of channels

Question 10

What is bronchiectasis?

Answer 10

It is abnormal dilation of the bronchioles, leading to excess mucus build up

Question 11

What are the 3 type of CFTR regulators used to treat CF, and what are some examples of each?

Answer 11

1. Potentiators - ivacaftor
2. Correctors - lumacaftor
3. Combination - 1+2, or ivacaftor + tezacaftor, or ivacaftor + tezacaftor + elexacaftor

Question 12

How do potentiators & correctors work?

Answer 12

Potentiators

• Increase gating/conductance of CFTR channels
• Blockages are cleared & Cl- can pass

Correctors
- Increase the no. & function of channels

Question 13

What is the age range of usage for potentiators and combination drugs?

Answer 13

Potentiators:
- (>4/6 months)

Combinations:

• Ivacaftor + lumacaftor = >2years
• Ivacaftor + tezacaftor = >12 years
• Ivacaftor + tezacaftor + elexacaftor = >12 years

Question 14

Which drug is given to each of the classes of CF?

Answer 14

Class 1: no drug given; increase exercise, O2 nebulisers, antibiotics for mucus  
Class 2: potentiators 
Class 3: potentiators 
Class 4: correctors
Class 5: correctors
Class 6: combination

Question 15

What do amplifier drugs do?

Answer 15

They enhance CFTR production on the cell surface.

Question 16

What are other treatments option available to treat CF?

Answer 16

1. Stabilisers
2. Bypassing CFTR channel
3. Over-reading stop codon of protein, terminating CFTR translation
4. Gene editing
5. Stem cell therapy

Question 17

Which drug is used as a mucolytic agent?

Answer 17

Dornase alfa (or carbocisteine)