PSC2002/L08 Cystic Fibrosis II Flashcards
Give 3 approaches to treat the ‘basic anion permeability defect’ in CF.
CFTR modulator therapy
Genetic therapy
Alternate channel therapy
How much CFTR function needs to be restored in CF patients?
50% gives risk for pancreatitis, sinusitis, lung disease, ABPA
10% - CBAVD
5% - increased sweat Cl-, lung disease
1% - early pancreatic disease
How is a new therapy assessed in vivo? (3)
Lung function e.g., FEV(10)
Sweat Chloride (sweat test)
Others e.g., no. hospitalisations, BMI, quality of life
What is a secretory coil (sweat glands)?
Primary NaCl-rich isotonic secretion from acinar (CC) cells
Mostly Cl- secretion via TMEM16A
What is the absorptive duct (sweat glands)?
Transcellular NaCl absorption but not water, producing a hypotonic fluid
Both ENaC and CFTR involved in transcellular NaCl absorption
How is ion and fluid transport regulated in a normal sweat gland?
Mostly via ACh (control via hypothalamus) and catecholamines
Why is CF sweat salty?
NaCl isn’t reabsorbed due to faulty CFTR
Normal sweat concentration <60mM at maximal rates
In CF, can be as high as 120mM
Describe CFTR modulator therapy. (4)
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
What is the equation for total Cl- current?
I = N x Po x i
Total Cl- current = no. CFTR channels x CFTR channel gating x ion flux
Give the 5 stages of the CFTR discovery process in Vertex Pharmaceuticals.
High throughput screening
Medicinal chemistry
Biology activity in cell cultures
Animal studies
Human studies
Give 2 types of CFTR modulators in clinical use.
Potentiators
Correctors
Give 3 types of CFTR modulators that are still under development.
Termination suppressors
Amplifiers
Stabilisers
What is the role of potentiators? (3)
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
What does VX-770 do? (2)
Increases G551D CFTR channel activity (Po)
Increases opening of G551D channels via ATP-independent mechanism
What occurred in June 2011 regarding CF?
Phase III STRIVE trial in CF patients carrying a copy of G551D
What occurred in Jan 2012 regarding CF?
FDA approval of Kalydeco for 33 other gating and RF mutants
What is the role of correctors?
Promote processing of class II mutants to plasma membrane
What do vertex correctors do?
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
Give 2 examples of correctors.
Low temperature
4-phenylbutyrate (4-PB)
VX-809 (lumacaftor)
What is the role of VX-809?
Increases F508del CFTR at apical plasma membrane of human airway cells in vitro
Describe the Ussing experiments of VX-809.
48 hours VX-809 treatment of human airway cultures
Chloride secretion (I(T)) measured in Ussing chambers after stimulation with cAMP agonist
Why did phase II studies on patients homozygous for F508del treated with VX-809 show little effect on lung function of sweat chloride?
F508del-CFTR has at least 3 defects that need to be corrected
Requires a combination therapy of VX-770 & VX-809
Give 3 F508del-CFTR defects
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)
Describe the phase III results in VX-770 and VX-809. (2)
3% improvement in ppFEV(1)
30% reduction in pulmonary exacerbations/hospitalisations
When was Orkambi approved and what is it?
Double drug combination of VX-809 and VX-770
2015 by FDA
What triple combination therapy was brought out in 2018?
2 correctors + 1 potentiator
VX-445 (elexacaftor) + VX-661 (tezacaftor) + VX-770 (ivacaftor)
F508del/MF and F508del/F508del patients
Give 2 examples of CFTR modulators.
Ivacaftor
Orkambi
Symkevi
Kaftrio
What is the basic defect in CF? (2)
Lack of epithelial anion (Cl- & HCO3-)
Fluid secretion
