advances in respiratory treatment - cystic fibrosis

Question 1

cystic fibrosis

Answer 1

highest prevalence in Europe, North America, Australia

autosomal recessive genetic disorder

caused by mutation of cystic fibrosis transmembrane conductance regulator CFTR

Question 2

mutation of cystic fibrosis transmembrane conductance regulator CFTR effects

Answer 2

lung function, secretory organs including pancreas

semen secretion so effects fertility

Question 3

what is the cystic fibrosis transmembrane conductance regulator CFTR

Answer 3

chloride-conducting transmembrane channel which regulates anion transport and mucociliary clearance in airways

regulates how thick mucus is

Question 4

mechanism of action of CFTR

Answer 4

CFTR promotes effluc of chloride ions inside to outside cells, down the electrochemical gradient

omosis - water follows out the cell, dilutes mucus and makes it easier to move and coughed out/ ingested

Question 5

CFTR genetic defects

Answer 5

mucus thickens

mucus retention as cilia cant move it out, inc likelihood of infection

Question 6

CFTR is part of the ____ family

Answer 6

ATP binding cassette (ABC) that push ions out of cells

but

chloride ions flow, not pushed as often are in ABCs - called broken ABC transporter

(ideal)

Question 7

what can abnormally thick mucus cause

Answer 7

chronic inflammation caused by bacterial lung infection, leading to accumulation of neutrophils in affected area

Question 8

main cystic fibrosis treatment strategy

Answer 8

airway clearance - get mucus out of lungs

Question 9

methods of airway clearance

Answer 9

percussion, vibration, deep breathing, forced coughing

Question 10

pharmacotherapies for cystic fibrosis (3)

Answer 10

antibiotic therapies for infection

mucolytics

CFTR modulators

Question 11

what are mucolytics

Answer 11

mucus thinners

Question 12

lungs of people with cystic fibrosis most commonly become infected by

Answer 12

pseudomonas aeruginosa

leads to pneumonia

length/ quality of life dec if cf infected with pseudomonas at young age

Question 13

chronic lung infection

Answer 13

accelerate declining lung function

need for lung transplant

respiratory failure

death

Question 14

example of antibiotic given long term to reduce infection

Answer 14

azithromycin

Question 15

after neutrophils die (naturally or via antibiotics)

Answer 15

inc thick mucus

aka after immune system function, thick mucus

after neutrophils die, DNA in mucus further inc thickness

Question 16

mucolytic first line treatment example

Answer 16

dornase alfa

Question 17

what is dornase alfa

Answer 17

purified recombinant human deoxyribonuclease (rhDNase)

enzyme that cleaves DNA in mucus of CF patients via hydrolysis

reduces viscosity in lungs, promotes mucus clearance

Question 18

how many classes are there of CFTR mutation

Answer 18

6

Question 19

CFTR modulators deal with the

Answer 19

cause of CF while others deal with symptoms

Question 20

what is the 1st type of CFTR mutation

Answer 20

biosynthesis

e.g. frameshift, splicing, nonsense mutations

gene cannot produce full, functional CFTR protein

Question 21

what is the 2nd type of CFTR mutation

Answer 21

folding and trafficking

misfolded CFTR protein not transported/ trafficked to cell surface

Question 22

what is the 3rd type of CFTR mutation

Answer 22

CFTR channel gating

reduced or lack of CFTR opening

Question 23

what is the 4th type of CFTR mutation

Answer 23

CFTR channel conductance

e.g. misshapen pore reduces chloride movement

Question 24

what is the 5th type of CFTR mutation

Answer 24

reduced protein production

e.g. functional but not enough made due to altered promoters or splicing

Question 25

what is the 6th type of CFTR mutation

Answer 25

destabilised CFTR protein expressed but degraded more easily, short half life

Question 26

ivacaftor was approved by FDA in

Answer 26

2012

Question 27

ivacaftor

Answer 27

first in class novel drug approved of CFTR modulator increases probability that defective channel will be open, allows chloride ions to pass through channel pore, water to flow through, thin mucus works on class 3 mutations CFTR potentiator

Question 28

other drugs similar to CFTR modulator ivacaftor (3)

Answer 28

tezacaftor elexacaftor lumacaftor

Question 29

initially, ivacaftor was approved for use in CF patients with _____ mutations

Answer 29

type 3 551G to D mutations so, patients must be genotyped first expensive drug - £14,000 per month, not including screening and monitoring costs

Question 30

type 3 551G to D mutations are found in ____% of CF patients

Answer 30

approx 4 only 320 people in england who fit this criteria, 270 actually suitable (aged 6 or over)

Question 31

in ____, ivacaftor use was extended to include other gene mutations such as

Answer 31

july 2014 178G to R 549S to N 1244G to E 551G to S 1251S to N 1255S to P 1349G to D (still rare - 0.56% of mutations) 380 eligible patients in england

Question 32

tezacaftor

Answer 32

corrector to facilitate folding/ trafficking to cell surface effective in most common gene mutation in CFTR - Phe508del effective in 45% of patients CFTR corrector drugs type 2 mutations

Question 33

Phe508del mutation

Answer 33

prevent CFTR trafficking to membrane, found in 45% of CF patients

Question 34

tezacaftor can be given in combination with ivacaftor if there are multiple gene mutations. how do these work

Answer 34

tezacaftor promotes correct trafficking to membrane ivacoftor promotes opening of channel, allows Cl- efflux for longer type 2 and 3 mutations

Question 35

elexacaftor

Answer 35

CFTR corrector works at alternative binding site to tezacaftor on CFTR protein, further facilitates CFTR functionality at cell surface and trafficking

Question 36

elexacaftor and tezacaftor can be given in combination for a ____ effect

Answer 36

additive

Question 37

lumacaftor

Answer 37

CFTR corrector - improves CFTR protein folding for patients that are Phe508del CFTR homozygous (has 2 copies of same gene)

Question 38

ivacaftor and lumacaftor

Answer 38

no improvement unless given with ivacaftor - CFTR corrector combined with potentiator thus improved protein folding and trafficking

Question 39

triple therapy

Answer 39

ivacaftor, tezacaftor, elexacaftor aka two correctors, one potentiator newest CF therapy clinically approved available in europe since august 2020

Question 40

triple therapy is effective for ___% of CF patients

Answer 40

90

Question 41

type 1 mutation treatment

Answer 41

no protein to rescue so gene therapy technology is ideal in theory, gene editing technology not accurate enough - remove defective gene and replace

Question 42

onasemnogene abeparovovec

Answer 42

adeno-associated virus vector-based gene therapy

Question 43

onasemnogene abeparovovec was approved by FDA in

Answer 43

May 2019 for treating infant patients, once spinal muscular atrophy confirmed by genetic analysis

Question 44

onasemnogene abeparovovec is administered as

Answer 44

one time injection into vein to replace defective gene with functional gene

Question 45

translate bio in lexington launched a clinical trial utilising CFTR mRNA. approx __ adults will be assigned randomly to recieve this treatment or a placebo

Answer 45

40 in feb 2020, FDA granted fast track status into this research development

Question 46

the CFTR modulator ivacaftor can be used alone in patients with mutations such as

Answer 46

G511D

Question 47

the CFTR modulator ivacaftor and lumacaftor can be used in patients with mutations such as

Answer 47

homozygous Phe508del

Question 48

the CFTR modulator ivacaftor and tezacaftor can be used in patients with mutations such as

Answer 48

Phe508 del and homozygous Phe508del

Question 49

the CFTR modulator ivacaftor and tezacaftor and elexacaftor can be used in patients with mutations such as

Answer 49

at least one Phe508 allele

Question 50

personalised therapies in CF treatment - enteroids case study

Answer 50

patient derived enteroids (including defective CFTR) to test drug responses ex vivo e.g. thru 3d co culture - showed ivacaftor was beneficial

Question 51

personalised therapies in CF treatment - genotype driven therapy case study

Answer 51

patient aged 71 showed some CF mutations - genetic screening was negative for 32 mutations further molecular studies inder Cystic Fibrosis Foundation Mutation Analysis Program revreald 2 CFTR sequence abnormalities revealed via patient using 2-d and 3-d nasal cultures to characterise new mutations to guide therapu optimisation, esp for non-class0c CF symptoms

Question 52

treatments of cystic fibrosis summary - 9

Answer 52

antibiotic - azithromycin mucolytic - dornase alfa CFTR modulator - class 3 ivacaftor, class 2 tezacaftor, corrector elexacaftor (elex and teza can be used additively, triple therapy ivacaftor, tezacaftor, elexacaftor aka two correctors, one potentiator type 1 mutation treatment - no protein to rescue - gene therapy ideal but tech not developed enough yet stealing from others e.g. onasemnogene abeparovovec adeno-associated virus vector-based gene therapy personalised/ future: patient derived enteroids (including defective CFTR) to test drug responses ex vivo e.g. thru 3d co culture, Cystic Fibrosis Foundation Mutation Analysis Program finding new mutations esp if pt presenting with non cf like symptoms

Question 53

types of drugs for cystic fibrosis - 4

Answer 53

antibiotic therapies for infection mucolytics CFTR modulators future gene driven shit