Week 8

Question 1

What are the three Ethical models?

Answer 1

Utilitarian ethics - what is the majority?
Code of conduct - Doing your duty…
Virtue ethics - How does a decent person act?

Question 2

Ethical principles in genetic/ genomic healthcare?

Answer 2

Autonomy_difficult they might need help
Beneficence_ you might impact someone in the family
Non-maleficence _doing no harm
Justice

Question 3

Needs principles

Answer 3

People that need it the most

Question 4

Maximum principles

Answer 4

is the maximise wellbeing

Question 5

Combination principles

Answer 5

Combine maximum health with equal lifetime health expectancy

Question 6

Egalitarian principles

Answer 6

Humans are equally, should all get the same treatment

Question 7

Independent committees

Answer 7

Chairs 
At least 2 lay members 
Health and social care professionals 
Care providers 
Technical experts

Question 8

ICER

Answer 8

I - Incremental: extra, additional
C - Cost: How much do we have to pay?
E - Effectiveness: what do we get in (QALY)
R - Ratio: unit per unit e.g. km/h - we used cost per QALY

Question 9

What is QALY?

Answer 9

• Combines both length of life and health-related quality of life (QA) into a single measure of health gain
• The amount of time spent in a health state is weighed by the quality of life score attached to health state
• QoL is usually scored with ‘perfect health’=1 and death=0

Question 10

Consideration beyond efficacy

Answer 10

Shouldn’t just be about the relative costs and benefits alone

Question 11

What type of condition is cystic fibrosis?

Answer 11

Rare Autosomal recessive condition, life shortening disease, Affecting lungs, liver, gastrointestinal tract, sinuses, sweat, pancreas and the reproductive system.

Question 12

What causes the symptoms of Cystic Fibrosis?

Answer 12

An abnormally sticky mucus, which is caused by a defective Cystic Fibrosis Transmembrane conductance Regulator protein. Which is normally involved in pumping chloride ions.

Question 13

What causes cystic fibrosis in the airways?

Answer 13

Chloride secretion is diminished due to the absence or impaired CTFR, resulting in more sodium being absorbed in to the cell alongside water dehydrating the airway, which causes the thick sticky mucus

Question 14

What causes the salty skin in Cystic fibrosis?

Answer 14

The epithelial cells can’t reabsorb the chloride ions and therefore the sodium is also not reabsorbed.

Question 15

What is the Class I CFTR mutation?

Answer 15

It could be caused by nonsense, frameshift or a splice mutation. Leading to a premature stop codon, forming unstable truncated RNA which is degraded. No protein on surface. (16.4%)

Question 16

What is the Class II CFTR mutation?

Answer 16

Caused by a missence mutation or an amino acid deletion, leads to mis-folding, and get degraded (Known as a trafficking defect). No protein on surface. Phe508del (80%)

Question 17

What is the Class III CFTR mutation?

Answer 17

Caused by a missence mutation or an amino acid change. Means the channel can’t open or close.

Question 18

What is the Class IV CFTR mutation?

Answer 18

Caused by a missence mutation or amino acid change. Meaning there is decreased channel conductance of chloride ions.

Question 19

What is the Class V CFTR mutation?

Answer 19

Caused by a splicing defect or a missence mutation. Get reduced amount of the correct protein, so there is less on the surface.

Question 20

What is the Class VI CFTR mutation?

Answer 20

Caused by a missence mutation and amino acid change. the protein works and is produced however doesn’t retain membrane stability.

Question 21

What was the older treatments of CFTR?

Answer 21

Treating the symptoms, such as antibiotics, keeping up to date on flu jabs, digestive system, diet and nutrition. airway clearance and lung transplant

Question 22

What are the targets cystic fibrosis?

Answer 22

Reduction in protein function in the class 3 and 4 CFTR mutations, potentiators. 
Reduction in amount of Type 1, 2, 5, 6 such as correctors and production correctors.

Question 23

What are potentiators as a target for class 3 and 4 CFTR mutations?

Answer 23

Increase the activity of defective CFTR at the cell surface. Potentiators can either act on gating or conductive defects

Question 24

What are the correctors as a target for class 1, 2, 5, and 6 CFTR mutations?

Answer 24

Overcome defective protein processing that normally results in the production of mis-folded CFTR. This allows increased trafficking of CFTR to the plasma membrane.

Question 25

What are production correctors as a target for class 1, 2, 5 and 6 CFTR mutations?

Answer 25

Instruct ribosomes to read through premature termination codons during mRNA translation.

Question 26

How was Ivacaftor/Kaleydeco/VX-770 found and what was its target?

Answer 26

High throughput screening using fluorescence membrane potential assay to identify potentiator assay. Made by vertex. First evidence found in 2008, Targets Class 3 and 4 mutations.

Question 27

In 2011 who was Ivacaftor given to?

Answer 27

Only patients with the G551D mutation (Class 3) initially for patients aged 12 and above, then they reduced the age, then it was offered to patients with other mutations.

Question 28

What were the clinical effects of Ivacaftor on class 3 patients(short trial)?

Answer 28

10% Increase in lung function 
Weight gain 
Decreased pulmonary excaberations 
Decreased sweat chloride concentration 
Decreased endobronchial colonisation with P.aeruginosa.

Question 29

What was the first corrector found for CFTR mutation II, which was good in vitro not in trials?

Answer 29

VX-Lumicaftor, high throughput screening

Increases number of proteins that are trafficked to cell surface, still missfolded

Question 30

Why did they combine Ivacaftor and lumicaftor and what drug did it make?

Answer 30

Called Orkambi, As the lumicaftor got it to the membrane but it could still not open and close, of which Ivacaftor, helped facilitate the opening and closing.

Question 31

Why was Orkambi licensed but not approved for use 2017?

Answer 31

nice rejected its use on the NHS as it costed £104,000 per year per patient.
ICER £218,448 per QALY Above threshold. Vertex allowed seriously ill patients to have it from the company. 24th of October it was accepted

Question 32

What were the problems with Orkambi?

Answer 32

Lumicaftor causes a CYPA4 gene induction, which metabolises Ivacaftor, Less Ivacaftor in system, therefore they do not work well together.

Question 33

What is tezacaftor?

Answer 33

New Corrector used in Symdeko, which was the new and improved from Orkambi.

Question 34

Why did they end up using two tezacaftor correctors and what were they?

Answer 34

VX-445 and VX-659

Because it increased the amount of protein at the surface

Question 35

What is the drug Ataluren -Translarna?

Answer 35

It binds to the ribosome of a cell and causes the ability to read through stop codons, so it will still produce the complete protein, it didn’t manage to improve lung function.

Question 36

What else was Atatluren previously used for?

Answer 36

Using in children with Duchenne muscular dystrophy, as it is also caused by premature stop codons.