PSC2002/L08 Cystic Fibrosis II

Question 1

Give 3 approaches to treat the ‘basic anion permeability defect’ in CF.

Answer 1

CFTR modulator therapy
Genetic therapy
Alternate channel therapy

Question 2

How much CFTR function needs to be restored in CF patients?

Answer 2

50% gives risk for pancreatitis, sinusitis, lung disease, ABPA
10% - CBAVD
5% - increased sweat Cl-, lung disease
1% - early pancreatic disease

Question 3

How is a new therapy assessed in vivo? (3)

Answer 3

Lung function e.g., FEV(10)
Sweat Chloride (sweat test)
Others e.g., no. hospitalisations, BMI, quality of life

Question 4

What is a secretory coil (sweat glands)?

Answer 4

Primary NaCl-rich isotonic secretion from acinar (CC) cells
Mostly Cl- secretion via TMEM16A

Question 5

What is the absorptive duct (sweat glands)?

Answer 5

Transcellular NaCl absorption but not water, producing a hypotonic fluid
Both ENaC and CFTR involved in transcellular NaCl absorption

Question 6

How is ion and fluid transport regulated in a normal sweat gland?

Answer 6

Mostly via ACh (control via hypothalamus) and catecholamines

Question 7

Why is CF sweat salty?

Answer 7

NaCl isn’t reabsorbed due to faulty CFTR
Normal sweat concentration <60mM at maximal rates
In CF, can be as high as 120mM

Question 8

Describe CFTR modulator therapy. (4)

Answer 8

Use chemicals to ‘correct’ mutant CFTR
Can be used alone or in combination with genetic therapies or alternate channel therapy
Required effect demands on mutation
Designer therapy may be required

Question 9

What is the equation for total Cl- current?

Answer 9

I = N x Po x i
Total Cl- current = no. CFTR channels x CFTR channel gating x ion flux

Question 10

Give the 5 stages of the CFTR discovery process in Vertex Pharmaceuticals.

Answer 10

High throughput screening
Medicinal chemistry
Biology activity in cell cultures
Animal studies
Human studies

Question 11

Give 2 types of CFTR modulators in clinical use.

Answer 11

Potentiators
Correctors

Question 12

Give 3 types of CFTR modulators that are still under development.

Answer 12

Termination suppressors
Amplifiers
Stabilisers

Question 13

What is the role of potentiators? (3)

Answer 13

Increase activity (Po) of class III gating mutants and some RF mutants
By increasing opening rate or duration of openings
Channels need to be phosphorylated for potentiators to work

Question 14

What does VX-770 do? (2)

Answer 14

Increases G551D CFTR channel activity (Po)
Increases opening of G551D channels via ATP-independent mechanism

Question 15

What occurred in June 2011 regarding CF?

Answer 15

Phase III STRIVE trial in CF patients carrying a copy of G551D

Question 16

What occurred in Jan 2012 regarding CF?

Answer 16

FDA approval of Kalydeco for 33 other gating and RF mutants

Question 17

What is the role of correctors?

Answer 17

Promote processing of class II mutants to plasma membrane

Question 18

What do vertex correctors do?

Answer 18

Improve processing of mutant CFTR from ER to Golgi by increasing folding efficiency of channel in ER
Mutant CFTR escape ER-quality control (ERQC) and isn’t degraded
Rescued CFTR (rCFTR) traffics to apical membrane, increasing number of channels (N) and anion secretion

Question 19

Give 2 examples of correctors.

Answer 19

Low temperature
4-phenylbutyrate (4-PB)
VX-809 (lumacaftor)

Question 20

What is the role of VX-809?

Answer 20

Increases F508del CFTR at apical plasma membrane of human airway cells in vitro

Question 21

Describe the Ussing experiments of VX-809.

Answer 21

48 hours VX-809 treatment of human airway cultures
Chloride secretion (I(T)) measured in Ussing chambers after stimulation with cAMP agonist

Question 22

Why did phase II studies on patients homozygous for F508del treated with VX-809 show little effect on lung function of sweat chloride?

Answer 22

F508del-CFTR has at least 3 defects that need to be corrected
Requires a combination therapy of VX-770 & VX-809

Question 23

Give 3 F508del-CFTR defects

Answer 23

Processing defect (low N)
Gating defect (lower Po than WT)
Rescued F508del CFTR has shorter resident time (stability) in plasma membrane (20 mins compared to 2 hours)

Question 24

Describe the phase III results in VX-770 and VX-809. (2)

Answer 24

3% improvement in ppFEV(1)
30% reduction in pulmonary exacerbations/hospitalisations

Question 25

When was Orkambi approved and what is it?

Answer 25

Double drug combination of VX-809 and VX-770
2015 by FDA

Question 26

What triple combination therapy was brought out in 2018?

Answer 26

2 correctors + 1 potentiator
VX-445 (elexacaftor) + VX-661 (tezacaftor) + VX-770 (ivacaftor)
F508del/MF and F508del/F508del patients

Question 27

Give 2 examples of CFTR modulators.

Answer 27

Ivacaftor
Orkambi
Symkevi
Kaftrio

Question 28

What is the basic defect in CF? (2)

Answer 28

Lack of epithelial anion (Cl- & HCO3-)
Fluid secretion