lecture 8/9 - CF part 2

Question 1

sweating

Answer 1

secretory coil duct epithelium: NaCl rich isotonic secretion from acinar cells (mostly Cl secretion via TMEM16A.
reabsorptive duct epithelium: secretion travels up the duct and ductal cells reabsorb salt but leave water producing a hypotonic (low solute level) solution. body is conserving salt and water goes to skin to cool body down.

Question 2

sodium transport drives the chloride transport back into the body. water cannot follow

Answer 2

in CF, you cant absorb sodium chloride causing sweat to be salty. allows us to test for CFTR function in patients

Question 3

gene therapy

Answer 3

can use viral vectors or liposome vectors
problems - physical and immune response
liposome (no immune response but less efficient)

Question 4

CFTR modular therapy

Answer 4

use drugs to correct mutant CFTR

Question 5

N x Po x i

Answer 5

N (class II - increase the number of CFTR channels at the surface)
Po (class III - improve CFTR channel gating, how long the channel is open for)
i (class IV - increase ion flux, the amount of chloride ions passed through the channel)

Question 6

we have two types of CFTR modulators

Answer 6

potentiators and correctors

Question 7

potentiators (increase gating)

Answer 7

designed for class III where theres no function (the channels are there but they dont gate)
e.g. ivacaftor (vertex VX-770)

Question 8

VX-770 increases

Answer 8

G551D CFTR channel activity (Po)

Question 9

correctors

Answer 9

chemicals that promote processing of class II mutants (e.g. f508del) to the plasma membrane
e.g. lumacaftor (VX-809)

Question 10

amiloride is a _____ blocker

Answer 10

ENaC

Question 11

VX-809 showed little effect on lung funtion or sweat chloride because

Answer 11

f508del has at least 3 defects to be corrected
1. processing defect (misfolding)
2. gating defect (low Po) when in membrane
3. f508del has shorter resident time in the plasma membrane (2 hrs compared to ~20 hrs)

Question 12

ivacaftor and lumacaftor combined was approved by FDA

Answer 12

called Orkambi. not approved in the UK

Question 13

VVX-661-tezacaftor was made and it was combined with ivacaftor, improvement on VX809

Answer 13

called symdeko

Question 14

triple therapy

Answer 14

combined VX445 (elexacaftor) with VX661 and VX770 for f508del patients
good results
2 correctors and 1 potentiator
called trikafta

Question 15

other CFTR modulators not in use

Answer 15

termination suppressors (for stop mutations)
amplifiers (when there isn’t enough protein)
stabilisers (keeps them in membrane longer)

Question 16

termination suppressors (class I)

Answer 16

drugs to trick ribosome into not seeing the stop mutation (ataluren)
ataluren didn’t improve FEV, still in clinical trails

Question 17

alternative channel therapy

Answer 17

this would be independent of the type of CF mutation so would benefit everyone with CF
1. use alternative chloride channels (ACCs) that are 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

Question 18

main ACC target

Answer 18

is TMEM16A which produces some anion and fluid secretion in CF cells when activated by agonists such as ATP and UTP

Question 19

decrease ENaC activity

Answer 19

1. use amiloride like drugs
2. target ENaC regulation (e.g splunc1)