L30- Future Treatment Flashcards
Which drug which was for duchenne muscular dystrophy was studied for class 1 mutations (brodlie et Al 2015)
Ataluren
How many have class 1 mutations
5-10%
What did ataluren propose to do
Help ribosomes skip over the ptc due to the nonsense mutation class 1 in CFTR. This made a functional CFTR protein
What was found in the first clinical trials
Increased expression of CFTR in basal epi cells when administered and no adverse effects
Why was ataluren not marketed
In phase 3 found no fev1 change or sweat Cl in patients
Modulators aren’t cures. What is
Gene therapy
What is the major issue with Gene therapy
The viral and non viral vectors can have issues when administered and sometimes not tolerated by body
What is a non viral vector example
Liposomes which are fat droplets
What is a good thing about then
When inhaled or nebulised spray they can easily be absorbed into the cell membrane and nucleus
In what patients did fev increase in first trials with liposomes
Only with severe diseqse
Why was it discontinued
Not as good as modulators and the fev1 showed fluctuation
Which article discusses different vectors for gene therapy
Burnley 2012
Why was adenovirus not a good idea
Causes inflammation and toxicity signs in the clinical trials
Why was adeno associated viruses AAV used instead but why did it fail
Less pathogenic but we’re too small to package the CFTR gene
Which type of virus was good because can target both non dividing and dividing cells
Lentiviruses
What was the flaw with lentiviruses
Have no receptor they bind to in airways. Needed to be made from fusing another viruses ha and fusion protein
Which 3 ways of gene editing are there
Talen - a re which is engineered to cleave specific sequence
Zfn nucleases
Crispr cas 9
Grna and cas9 used to target and cleave dna but what does it depend on to rearrange the healthy gene in
HDR or NHEJ
Why is mucociliary clearance strategies still neeedd
Still class 1,5 and 6 struggling
Name some types
Hypertonic saline
Dornase Alfa
Inhaled mannitol
What is dornase alfa
The DNase cleaving dna in mucus and sputum and reduces viscosity
Which article discusses hypertonic saline
Elkins 2006
What does hypertonic saline do
Increase fev and fvc
Reduced exacerbations too
Increased hydration of asl, transportation of sputum and cough induction
Without major cost or side effect
Which enac channel inhibitor was promising found in ussing chamber ion movement
Spx-101
What did it do in early clinical trials before seeing no lung function change in clinical phases
Showed increased mucociliary clearance and reduced inflammation in sheep
Which cacc channel was found promising in ussing chamber experiments and what channel does it have
Tmem16a
Has a cl HCO exchanger (augments Cl release)
Which drug Tmem16a made it through preclinical trials and why
Denufosol
Improved ciliary and mucociliary functions
Why did clinical trials see no long term effect of denufosol
It’s a short acting channel compared to CFTR
Which article discusses Tmem16a potentiation
Danahay et Al 2019
How did denufosol work and had no long term effects
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
Why are other potnetiators being looked at for longer Tmem16a potentiation
Ones that increase the activation of tmem16a from already endogenous stimuli
Which therapies are for anti inflam and infection
Ibuprofen and for infection eg azithromycin antibiotics
