Lecture 10 - Cystic Fibrosis

Question 1

What is cystic fibrosis?

Answer 1

A rare, autosomal recessive disorder which affects all mucous-lined endothelial organs (lungs, GI tract, pancreas, sweat ducts, liver) by production of thick and sticky mucus

Question 2

What is the pathology of cystic fibrosis?

Answer 2

Dysfunctional or lack of the CF Transmembrane conductance Regulator protein (CFTR)
In the lungs there is less Cl- secretion, so increased Na+ and water reabsorption

Question 3

What are the 6 classes of CFTR mutation?

Answer 3

Type I: truncated RNA is unstable, gets degraded
Type II: protein misfolded and degraded
Type III: CFTR channel is not activated correctly
Type IV: CFTR channel has decreased conductance
Type V: splicing defects means some RNA non functional, fewer overall CFTR proteins
Type VI: deceased CFTR membrane stability

Question 4

Which is the most prevalent CFTR mutation and what percentage of CF sufferers does it affect?

Answer 4

Type II

80%

Question 5

What are some of the past treatments for CF?

Answer 5

Bronchodilators
Corticosteroids
Vaccinations, altered diet
Physiotherapy for airway clearance
Lung transplants

Question 6

What are the 3 newer classes of treatment for CF? What does each do?

Answer 6

Potentiators - acts on gating or conductance defects
Correctors - improves processing and delivery of functional CFTR proteins to the cell surface
Production correctors - can instruct ribosomes to read through premature stop codons

Question 7

Name an example of a potentiator treatment. What type of mutation is this meant for?

Answer 7

Ivacoftor

Meant for type III mutations

Question 8

Name 2 limitations of Ivacoftor

Answer 8

Effective only for people with ONE type III mutation

Limited patient impact because type III mutations are quite rare

Question 9

Name an example of a corrector treatment

Answer 9

Lumicaftor

Question 10

Why is Lumicaftor not used?

Answer 10

Not effective alone - improves hypertonic sweating but not lung function

Question 11

Name a combination treatment for CF. Who is it effective for?

Answer 11

Ivacoftor + Lumicaftor = Orkambi

Effective for people with type II mutations

Question 12

Why is Orkambi not used?

Answer 12

NICE rejected its use on the NHS due to very high cost

Question 13

Name an example of a production corrector treatment

Which mutation type is it meant for?

Answer 13

Ataluren

For Type I mutations

Question 14

Why is Ataluren not used?

Answer 14

Effective for muscular dystrophy but not shown to be effective for CF

Question 15

How does Orkambi work?

Answer 15

Lumicaftor helps to get the misfolded protein to the cell membrane
Ivacoftor then helps it to open/close properly