L30- Future Treatment

Question 1

Which drug which was for duchenne muscular dystrophy was studied for class 1 mutations (brodlie et Al 2015)

Answer 1

Ataluren

Question 2

How many have class 1 mutations

Answer 2

5-10%

Question 3

What did ataluren propose to do

Answer 3

Help ribosomes skip over the ptc due to the nonsense mutation class 1 in CFTR. This made a functional CFTR protein

Question 4

What was found in the first clinical trials

Answer 4

Increased expression of CFTR in basal epi cells when administered and no adverse effects

Question 5

Why was ataluren not marketed

Answer 5

In phase 3 found no fev1 change or sweat Cl in patients

Question 6

Modulators aren’t cures. What is

Answer 6

Gene therapy

Question 7

What is the major issue with Gene therapy

Answer 7

The viral and non viral vectors can have issues when administered and sometimes not tolerated by body

Question 8

What is a non viral vector example

Answer 8

Liposomes which are fat droplets

Question 9

What is a good thing about then

Answer 9

When inhaled or nebulised spray they can easily be absorbed into the cell membrane and nucleus

Question 10

In what patients did fev increase in first trials with liposomes

Answer 10

Only with severe diseqse

Question 11

Why was it discontinued

Answer 11

Not as good as modulators and the fev1 showed fluctuation

Question 12

Which article discusses different vectors for gene therapy

Answer 12

Burnley 2012

Question 13

Why was adenovirus not a good idea

Answer 13

Causes inflammation and toxicity signs in the clinical trials

Question 14

Why was adeno associated viruses AAV used instead but why did it fail

Answer 14

Less pathogenic but we’re too small to package the CFTR gene

Question 15

Which type of virus was good because can target both non dividing and dividing cells

Answer 15

Lentiviruses

Question 16

What was the flaw with lentiviruses

Answer 16

Have no receptor they bind to in airways. Needed to be made from fusing another viruses ha and fusion protein

Question 17

Which 3 ways of gene editing are there

Answer 17

Talen - a re which is engineered to cleave specific sequence

Zfn nucleases

Crispr cas 9

Question 18

Grna and cas9 used to target and cleave dna but what does it depend on to rearrange the healthy gene in

Answer 18

HDR or NHEJ

Question 19

Why is mucociliary clearance strategies still neeedd

Answer 19

Still class 1,5 and 6 struggling

Question 20

Name some types

Answer 20

Hypertonic saline

Dornase Alfa

Inhaled mannitol

Question 21

What is dornase alfa

Answer 21

The DNase cleaving dna in mucus and sputum and reduces viscosity

Question 22

Which article discusses hypertonic saline

Answer 22

Elkins 2006

Question 23

What does hypertonic saline do

Answer 23

Increase fev and fvc

Reduced exacerbations too

Increased hydration of asl, transportation of sputum and cough induction

Without major cost or side effect

Question 24

Which enac channel inhibitor was promising found in ussing chamber ion movement

Answer 24

Spx-101

Question 25

What did it do in early clinical trials before seeing no lung function change in clinical phases

Answer 25

Showed increased mucociliary clearance and reduced inflammation in sheep

Question 26

Which cacc channel was found promising in ussing chamber experiments and what channel does it have

Answer 26

Tmem16a

Has a cl HCO exchanger (augments Cl release)

Question 27

Which drug Tmem16a made it through preclinical trials and why

Answer 27

Denufosol

Improved ciliary and mucociliary functions

Question 28

Why did clinical trials see no long term effect of denufosol

Answer 28

It’s a short acting channel compared to CFTR

Question 29

Which article discusses Tmem16a potentiation

Answer 29

Danahay et Al 2019

Question 30

How did denufosol work and had no long term effects

Answer 30

Bound to p2y2 receptors and increased ic calcium whcih triggered the tmem16a channel to release Cl

Ended up desensitising the receptor and depleting ca stores

Question 31

Why are other potnetiators being looked at for longer Tmem16a potentiation

Answer 31

Ones that increase the activation of tmem16a from already endogenous stimuli

Question 32

Which therapies are for anti inflam and infection

Answer 32

Ibuprofen and for infection eg azithromycin antibiotics