lecture 9 Flashcards

1
Q

what is CFTR modulator therapy - vertex?

A

identifies drugs to restore function to mutant CFTR
required effect depends on mutation

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2
Q

what are the 5 types of CFTR modulators?

A
  1. potentiators -> improve response
  2. correctors -> correct trafficking defect
  3. termination suppressors
  4. amplifiers
  5. stabilisers
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3
Q

how do potentiators work?

A

-increase opening rate/ number of openings/ duration of openings
-so increases activity of mutant CFTR
-channels need to be phosphorylated for potentiators to work

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4
Q

what do potentiators increase the activity of?

A

class III gating mutants and some RF mutants

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5
Q

what are the different types of potentiators?

A

-natural = genistein
-man made = vertex VX-770

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6
Q

what does VX-770 do?

A

-increases G551D CFTR channel activity
-increases opening via ATP-independent mechanism

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7
Q

how is the activity of VX-770 tested?

A

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

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8
Q

what results were found?

A

-brief openings
-low activity
-when concentration increased, opening remained longer

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9
Q

what did the phase III STRIVE trial show?

A

-increase in efficacy with ivocaftor treatment
-sweat chloride decreased with higher concentrations -changing it to a non CF value

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10
Q

what are correctors?

A

-chemicals that correct the processing/trafficking problem the F508del mutation has
-increase number of CFTR channels in apical plasma membrane
-help class II mutants

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11
Q

what are the features needed for correctors to be used?

A

-low temperature (increases trafficking)
-eg. lumacaftor

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12
Q

what do vertex correctors do?

A

-improve processing of mutant CFTR from ER to golf
-increases folding efficacy of mutant channel in ER

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13
Q

what does mutant CFTR do?

A

-escapes ER-quality control machinery and is now not degraded

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14
Q

what does the rescued CFTR do?

A

-traffics to apical membrane
-increases number of channels
-increases anion secretion

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15
Q

what are the 3 defects that F508del-CFTR has?

A
  1. processing defect
  2. gating defect (lower Po than wild type)
  3. rescued F508del CFTR has shorter resident time (stability) in plasma membrane - lower half life
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15
Q

what results were recorded from phase II studies? (in cells)

A

-tested on patients that are homozygous for F508del
-showed little effect on lung functioning sweat chloride

16
Q

what two drugs were combined?

A

VX-770 and VX-809 (ivocaftor and lumocaftor)

17
Q

what are the phase III results for the combination therapy?

A

improvement in FEV
reduction in pulmonary exacerbations and hospitalisations
= orkambi
uk didn’t initially approve because of cost/benefit

18
Q

what is the triple combination therapy?

A

2 correctors and 1 potentiator
-thought to improve folding
-tested on minimal function mutations
-sweat chloride decreased
-hospitalisations decreased
-BMI improved

19
Q

what are read through agents for?

A

class I premature termination mutations

20
Q

what would amplifiers do?

A

improve amount protein you get in cell
class V

21
Q

what is alternate channel therapy?

A

-indepednent of CF mutation as doesnt target CFTR

22
Q

how does alternate channel therapy work?

A
  1. uses alternative chloride channels (ACCs) present in CF cells to bypass defective CFTR and restore Cl-/HCO3- and fluid transport
  2. use inhibitors of ENaC to help reduce salt and fluid absorption
23
Q

what is the issue with increasing ENaC?

A

important in blood pressure
so needs to be localised to lung t avoid kidney problems

25
Q

what is the function of TMEM16A?

A

chloride channel
-activation increases Cl- and fluid secretion in CF airway cells by agonists like ATP and UTP
-ATP/UTP released from epithelial cells into ASL during normal breathing cycles
-bind to purinergic receptors to increase cytosolic Ca2+ - then activating TMEM16A

26
Q

how does ATP and UTP work?

A

-released from cells into ASL
-bind to GPCR
-cause increase in calcium

27
Q

how do you decrease ENaC activity?

A
  1. using amiloride like drugs
  2. target ENaC regulation (inhibiting proteases, target ENaC regulatory proteins)
28
Q

what are some other approaches?

A

-synthetic anion channels and transporters (anionophores)
eg. amphotericin (antifungal that transports chloride and bicarbonate)
-targets H+ATPase in airway cells that acidifies the ASL