L11 - genetic determinants of lung function/personalised medicine Flashcards
CF genetics
autosomal recessive
defect in long arm of chromosome 7 coding for CFTR protein
CFTR mutations
over 1600 mutations
F508del mutation
causes CFTR 44% homozygous
CF carrier ratio
1:25
CF birth ratio
1:25,000
CFTR protein
transport protein on membrane of epithelial cells for chloride and thiocyanate ions
Normal CFTR protein
moves chloride ions to the outside of the cell
Mutant CFTR protein
does not move chloride ions, causing sticky mucus to build up on the outside of the cell
Abnormal CFTR protein leads to…
Dysregulated epithelial fluid transport, leading to thickened secretions in a number of organs
% in lung and GI involvement
80%
% in lung alone
15
Failure of mucocilliary clearance leads to…
with impaired immune function this contributes to continued insult to the bronchial wall, through the recruitment of inflammatory cells and uncontrolled neutrophilic inflammation
Pathophysiology flow chart
- Microbial insults
- Defect in host defence
- Respiratory tract infection
- bronchial inflammation
- Respiratory tract damage
- progressive lung disease
Bronchitis leads to
Bronchiectasis resulting in fibrosis
Clinical symptoms
Frequent infections, malabsorption, failure to thrive
Abnormal salt/chloride exchange
raised skin salt and impaired nasal potential difference
% diagnosed by 6 months
50%
% diagnosed by 8 years
90%
Normal symptoms
fatigue, chronic cough, recurrent URIs, thick mucus, chronic hypoxia, decreased absorption of vitamins and enzymes, abdominal distention, decreased digestive enzymes, rectal prolapse, meconium ileum in newborns
Treatments
increased calories and protein, chest physiotherapy, breathing exercises and aerosol therapy
Medications
antibiotics, supplement vitamins, aerosol bronchodilators, mucolytics and pancreatic enzymes
Bromchiectasis
90% surviving neonatal period
Infertility in males
98%
Infertility n females
20%
Pancreatic insufficency
malabsorption 85%
CF-related diabetes
50% by age 30
CF chronic liver disease
25%
Cirrhosis
10%
Sinonasal polyps
10-25%
Distal intestinal obstruction syndromex
20%
Arthropathy
10% adults
Meconium ileus
10-20% in infants
Low bone mineral density
10-25%
Pneumothorax
4-20%
Allergic lung disease
7%
Rescue antibiotics
2 week course
access is central/peripheral
home vs. hospital
issued with frequent antibiotics = allergies, renal impairment, resistance and access problems
CF prevention management
segregation, surveillance, eradication infections early, antibiotics, airway clearance physiotherapy, bronchodilator and exercise, psychosocial sport, vaccinations, potentially lung transplant
Nutrition prevention
pancreatic enzymes, diet high calories and fat, supplements including vitamins, percutaneous feeding
Personalised medicine
individual tailored medicine, stratified based on predicted response or risk of disease, genetic information major factor
Personalised medicine advantages
increased adherence to treatment, improved quality of life, prolongs life, help avoid adverse drug reactions/intolerances, shift the emphasis in medicine from rescue to prevention, help control overall healthcare costs, direct selection of optimal therapy and reduce trial-and-error prescribing, reveal additional or alternative uses for medicines and drug candidates
Personalised medicine in CF
useful as it is a monogenic disorder, less known influence of environmental factors
Well characterised pathophysiology with clear therapeutic targets
Genotype-directed therapies
CF monogenic recessive diroder, malformed chloride pump leads to multi system disorder, different classes of defect
Class 1
not synthesised
Nonsense frameshift or splicing mutations
prevents biosynthesis
G542X
no synthesis
Class 2
Reduced trafficking, misfiling in the ER< leading to an absence of functional protein at the cell membrane
F508del
Reduced trafficking with ER misfolding
Class 3
reduced gating, CFTR protein reaches membrane but less opening
G551D
reduced gating
Class 4
decreased conductance, protein reaches cell membrane but abnormal conformation of the pore leading to disrupted ion flow
R117M
decreased conductance
Class 5
Reduced synthesis so less protein at the cell membrane
A455E
reduced synthesis
Ivacaftor
CFTR potentiator for class II mutations, i.e. G551D improves FEV1, MI and QoL
Potentiator
potentiates chloride secretion via increasing the CFTR channel opening time
Orkambi
Combined Ivacaftor and Lumacaftor Potentiator and corrector improves stabilisation and processing so more on cell surface Class II mutations only available on compassionate use
orkambi side effects
bronchospasm, GI upset and rash
CFTR correctors
corrects cellular misprocessing of CFTR to facilitate transport from the ER
improves stabilisation and processing to increase presence on cell surface
Symkevi/Symdeko
Combined Ivacaftor and Tezacaftor Corrector and potentiator Class II mutations compassionate use programme less side effects
Tripe therapy
VX445 and Symkevi
Corrector and potentiator
new drug
final results not known
Other agents under review
gene therapy, inhaled therapies and intravenous antibiotic therapies
Challenges treating CF
adherence to treatment, high treatment burden, high cost, allergies/intolerances, different infectious organisms and drug resistance, restrictions, prevention vs. rescue
Rescue treatment
disadvantages in terms of cost, time, decline in quality of life and life expectancy
side effects of recurrent intravenous antibiotic therapy
Treatment burden
physiotherapy, nebulisers, exercise, oral medications, oral supplements, percutaneous nutrition, insulin, intravenous antibiotics
Treatment burden time
all adds up to 2-4 hours treatment daily
Adherence to medication
amongst people with long-term conditions estimated at 30-50%
CF adherence to nebulisers
36%
