advances in respiratory treatment - cystic fibrosis Flashcards
cystic fibrosis
highest prevalence in Europe, North America, Australia
autosomal recessive genetic disorder
caused by mutation of cystic fibrosis transmembrane conductance regulator CFTR
mutation of cystic fibrosis transmembrane conductance regulator CFTR effects
lung function, secretory organs including pancreas
semen secretion so effects fertility
what is the cystic fibrosis transmembrane conductance regulator CFTR
chloride-conducting transmembrane channel which regulates anion transport and mucociliary clearance in airways
regulates how thick mucus is
mechanism of action of CFTR
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
CFTR genetic defects
mucus thickens
mucus retention as cilia cant move it out, inc likelihood of infection
CFTR is part of the ____ family
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)
what can abnormally thick mucus cause
chronic inflammation caused by bacterial lung infection, leading to accumulation of neutrophils in affected area
main cystic fibrosis treatment strategy
airway clearance - get mucus out of lungs
methods of airway clearance
percussion, vibration, deep breathing, forced coughing
pharmacotherapies for cystic fibrosis (3)
antibiotic therapies for infection
mucolytics
CFTR modulators
what are mucolytics
mucus thinners
lungs of people with cystic fibrosis most commonly become infected by
pseudomonas aeruginosa
leads to pneumonia
length/ quality of life dec if cf infected with pseudomonas at young age
chronic lung infection
accelerate declining lung function
need for lung transplant
respiratory failure
death
example of antibiotic given long term to reduce infection
azithromycin
after neutrophils die (naturally or via antibiotics)
inc thick mucus
aka after immune system function, thick mucus
after neutrophils die, DNA in mucus further inc thickness
mucolytic first line treatment example
dornase alfa
what is dornase alfa
purified recombinant human deoxyribonuclease (rhDNase)
enzyme that cleaves DNA in mucus of CF patients via hydrolysis
reduces viscosity in lungs, promotes mucus clearance
how many classes are there of CFTR mutation
6
CFTR modulators deal with the
cause of CF while others deal with symptoms
what is the 1st type of CFTR mutation
biosynthesis
e.g. frameshift, splicing, nonsense mutations
gene cannot produce full, functional CFTR protein
what is the 2nd type of CFTR mutation
folding and trafficking
misfolded CFTR protein not transported/ trafficked to cell surface
what is the 3rd type of CFTR mutation
CFTR channel gating
reduced or lack of CFTR opening
what is the 4th type of CFTR mutation
CFTR channel conductance
e.g. misshapen pore reduces chloride movement
what is the 5th type of CFTR mutation
reduced protein production
e.g. functional but not enough made due to altered promoters or splicing
what is the 6th type of CFTR mutation
destabilised CFTR protein
expressed but degraded more easily, short half life
ivacaftor was approved by FDA in
2012
ivacaftor
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
other drugs similar to CFTR modulator ivacaftor (3)
tezacaftor
elexacaftor
lumacaftor
initially, ivacaftor was approved for use in CF patients with _____ mutations
type 3 551G to D mutations
so, patients must be genotyped first
expensive drug - £14,000 per month, not including screening and monitoring costs
type 3 551G to D mutations are found in ____% of CF patients
approx 4
only 320 people in england who fit this criteria, 270 actually suitable (aged 6 or over)
in ____, ivacaftor use was extended to include other gene mutations such as
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
tezacaftor
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
Phe508del mutation
prevent CFTR trafficking to membrane, found in 45% of CF patients
tezacaftor can be given in combination with ivacaftor if there are multiple gene mutations. how do these work
tezacaftor promotes correct trafficking to membrane
ivacoftor promotes opening of channel, allows Cl- efflux for longer
type 2 and 3 mutations
elexacaftor
CFTR corrector
works at alternative binding site to tezacaftor on CFTR protein, further facilitates CFTR functionality at cell surface and trafficking
elexacaftor and tezacaftor can be given in combination for a ____ effect
additive
lumacaftor
CFTR corrector - improves CFTR protein folding
for patients that are Phe508del CFTR homozygous (has 2 copies of same gene)
ivacaftor and lumacaftor
no improvement unless given with ivacaftor - CFTR corrector combined with potentiator thus improved protein folding and trafficking
triple therapy
ivacaftor, tezacaftor, elexacaftor
aka two correctors, one potentiator
newest CF therapy clinically approved
available in europe since august 2020
triple therapy is effective for ___% of CF patients
90
type 1 mutation treatment
no protein to rescue
so gene therapy technology is ideal in theory, gene editing technology not accurate enough - remove defective gene and replace
onasemnogene abeparovovec
adeno-associated virus vector-based gene therapy
onasemnogene abeparovovec was approved by FDA in
May 2019
for treating infant patients, once spinal muscular atrophy confirmed by genetic analysis
onasemnogene abeparovovec is administered as
one time injection into vein to replace defective gene with functional gene
translate bio in lexington launched a clinical trial utilising CFTR mRNA. approx __ adults will be assigned randomly to recieve this treatment or a placebo
40
in feb 2020, FDA granted fast track status into this research development
the CFTR modulator ivacaftor can be used alone in patients with mutations such as
G511D
the CFTR modulator ivacaftor and lumacaftor can be used in patients with mutations such as
homozygous Phe508del
the CFTR modulator ivacaftor and tezacaftor can be used in patients with mutations such as
Phe508 del and homozygous Phe508del
the CFTR modulator ivacaftor and tezacaftor and elexacaftor can be used in patients with mutations such as
at least one Phe508 allele
personalised therapies in CF treatment - enteroids case study
patient derived enteroids (including defective CFTR) to test drug responses ex vivo e.g. thru 3d co culture - showed ivacaftor was beneficial
personalised therapies in CF treatment -
genotype driven therapy case study
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
treatments of cystic fibrosis summary - 9
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
types of drugs for cystic fibrosis - 4
antibiotic therapies for infection
mucolytics
CFTR modulators
future gene driven shit
