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342 > advances in respiratory treatment - cystic fibrosis > Flashcards

advances in respiratory treatment - cystic fibrosis Flashcards

1
Q

cystic fibrosis

A

highest prevalence in Europe, North America, Australia

autosomal recessive genetic disorder

caused by mutation of cystic fibrosis transmembrane conductance regulator CFTR

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2
Q

mutation of cystic fibrosis transmembrane conductance regulator CFTR effects

A

lung function, secretory organs including pancreas

semen secretion so effects fertility

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3
Q

what is the cystic fibrosis transmembrane conductance regulator CFTR

A

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

regulates how thick mucus is

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4
Q

mechanism of action of CFTR

A

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

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5
Q

CFTR genetic defects

A

mucus thickens

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

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6
Q

CFTR is part of the ____ family

A

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)

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7
Q

what can abnormally thick mucus cause

A

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

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8
Q

main cystic fibrosis treatment strategy

A

airway clearance - get mucus out of lungs

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9
Q

methods of airway clearance

A

percussion, vibration, deep breathing, forced coughing

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10
Q

pharmacotherapies for cystic fibrosis (3)

A

antibiotic therapies for infection

mucolytics

CFTR modulators

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11
Q

what are mucolytics

A

mucus thinners

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12
Q

lungs of people with cystic fibrosis most commonly become infected by

A

pseudomonas aeruginosa

leads to pneumonia

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

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13
Q

chronic lung infection

A

accelerate declining lung function

need for lung transplant

respiratory failure

death

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14
Q

example of antibiotic given long term to reduce infection

A

azithromycin

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15
Q

after neutrophils die (naturally or via antibiotics)

A

inc thick mucus

aka after immune system function, thick mucus

after neutrophils die, DNA in mucus further inc thickness

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16
Q

mucolytic first line treatment example

A

dornase alfa

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17
Q

what is dornase alfa

A

purified recombinant human deoxyribonuclease (rhDNase)

enzyme that cleaves DNA in mucus of CF patients via hydrolysis

reduces viscosity in lungs, promotes mucus clearance

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18
Q

how many classes are there of CFTR mutation

A

6

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19
Q

CFTR modulators deal with the

A

cause of CF while others deal with symptoms

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20
Q

what is the 1st type of CFTR mutation

A

biosynthesis

e.g. frameshift, splicing, nonsense mutations

gene cannot produce full, functional CFTR protein

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21
Q

what is the 2nd type of CFTR mutation

A

folding and trafficking

misfolded CFTR protein not transported/ trafficked to cell surface

22
Q

what is the 3rd type of CFTR mutation

A

CFTR channel gating

reduced or lack of CFTR opening

23
Q

what is the 4th type of CFTR mutation

A

CFTR channel conductance

e.g. misshapen pore reduces chloride movement

24
Q

what is the 5th type of CFTR mutation

A

reduced protein production

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

25
Q

what is the 6th type of CFTR mutation

A

destabilised CFTR protein

expressed but degraded more easily, short half life

26
Q

ivacaftor was approved by FDA in

A

2012

27
Q

ivacaftor

A

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

28
Q

other drugs similar to CFTR modulator ivacaftor (3)

A

tezacaftor
elexacaftor
lumacaftor

29
Q

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

A

type 3 551G to D mutations

so, patients must be genotyped first

expensive drug - £14,000 per month, not including screening and monitoring costs

30
Q

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

A

approx 4

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

31
Q

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

A

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

32
Q

tezacaftor

A

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

33
Q

Phe508del mutation

A

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

34
Q

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

A

tezacaftor promotes correct trafficking to membrane

ivacoftor promotes opening of channel, allows Cl- efflux for longer

type 2 and 3 mutations

35
Q

elexacaftor

A

CFTR corrector

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

36
Q

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

A

additive

37
Q

lumacaftor

A

CFTR corrector

for patients that are Phe508del CFTR homozygous (has 2 copies of same gene)

38
Q

lumacaftor monotherapy

A

no improvement unless given with ivacaftor

39
Q

triple therapy

A

ivacaftor, tezacaftor, elexacaftor

aka two correctors, one potentiator

newest CF therapy clinically approved

available in europe since august 2020

40
Q

triple therapy is effective for ___% of CF patients

A

90

41
Q

type 1 mutation treatment

A

no protein to rescue

so gene therapy technology is ideal in theory, gene editing technology not accurate enough - remove defective gene and replace

42
Q

gene-based therapy example for other disease

A

for spinal muscular atrophy (SMA)

onasemnogene abeparovovec

43
Q

onasemnogene abeparovovec

A

adeno-associated virus vector-based gene therapy

44
Q

onasemnogene abeparovovec was approved by FDA in

A

May 2019

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

45
Q

onasemnogene abeparovovec is administered as

A

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

46
Q

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

A

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

47
Q

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

A

G511D

48
Q

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

A

homozygous Phe508del

49
Q

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

A

Phe508 del and homozygous Phe508del

50
Q

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

A

at least one Phe508 allele

342 (21 decks)

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