lecture 9 Flashcards
what is CFTR modulator therapy - vertex?
identifies drugs to restore function to mutant CFTR
required effect depends on mutation
what are the 5 types of CFTR modulators?
- potentiators -> improve response
- correctors -> correct trafficking defect
- termination suppressors
- amplifiers
- stabilisers
how do potentiators work?
-increase opening rate/ number of openings/ duration of openings
-so increases activity of mutant CFTR
-channels need to be phosphorylated for potentiators to work
what do potentiators increase the activity of?
class III gating mutants and some RF mutants
what are the different types of potentiators?
-natural = genistein
-man made = vertex VX-770
what does VX-770 do?
-increases G551D CFTR channel activity
-increases opening via ATP-independent mechanism
how is the activity of VX-770 tested?
put G551D-CFTR channel into heterologous system
patch clamp the cell
inside out patch recording
inside of patch of Membrane is equivalent to cytoplasmic surface
what results were found?
-brief openings
-low activity
-when concentration increased, opening remained longer
what did the phase III STRIVE trial show?
-increase in efficacy with ivocaftor treatment
-sweat chloride decreased with higher concentrations -changing it to a non CF value
what are correctors?
-chemicals that correct the processing/trafficking problem the F508del mutation has
-increase number of CFTR channels in apical plasma membrane
-help class II mutants
what are the features needed for correctors to be used?
-low temperature (increases trafficking)
-eg. lumacaftor
what do vertex correctors do?
-improve processing of mutant CFTR from ER to golf
-increases folding efficacy of mutant channel in ER
what does mutant CFTR do?
-escapes ER-quality control machinery and is now not degraded
what does the rescued CFTR do?
-traffics to apical membrane
-increases number of channels
-increases anion secretion
what are the 3 defects that F508del-CFTR has?
- processing defect
- gating defect (lower Po than wild type)
- rescued F508del CFTR has shorter resident time (stability) in plasma membrane - lower half life
what results were recorded from phase II studies? (in cells)
-tested on patients that are homozygous for F508del
-showed little effect on lung functioning sweat chloride
what two drugs were combined?
VX-770 and VX-809 (ivocaftor and lumocaftor)
what are the phase III results for the combination therapy?
improvement in FEV
reduction in pulmonary exacerbations and hospitalisations
= orkambi
uk didn’t initially approve because of cost/benefit
what is the triple combination therapy?
2 correctors and 1 potentiator
-thought to improve folding
-tested on minimal function mutations
-sweat chloride decreased
-hospitalisations decreased
-BMI improved
what are read through agents for?
class I premature termination mutations
what would amplifiers do?
improve amount protein you get in cell
class V
what is alternate channel therapy?
-indepednent of CF mutation as doesnt target CFTR
how does alternate channel therapy work?
- uses alternative chloride channels (ACCs) present in CF cells to bypass defective CFTR and restore Cl-/HCO3- and fluid transport
- use inhibitors of ENaC to help reduce salt and fluid absorption
what is the issue with increasing ENaC?
important in blood pressure
so needs to be localised to lung t avoid kidney problems
