8. Cystic Fibrosis and CFTR related disorders

Question 1

What are CF modulators?

Answer 1

Small molecule drugs that bind to CFTR protein and correct function

Prevent development of organ damage related to ion and fluid imbalance

Do not fully restore chloride flow but improve flow enough to lessen symptoms

Question 2

What are the three classes of CF modulator?

Answer 2

1. Potentiators
2. Correctors
3. Amplifiers

Question 3

What is the common CF potentiator?

What mutations does it target?

Answer 3

Ivacaftor

Class 3 (channel regulation defect) and class 4 (decreased conductance) where primary protein defect is related to ion channel dysregulation

Question 4

How does ivacaftor work?

Answer 4

Binds to CFTR protein, increases time that mature channel is in open configuration –> increased transport activity

Question 5

What is the name of the common CF correctors?

What mutations do they target?

Answer 5

Lumacaftor, tezacaftor, elexacaftor

Mainly Phe508del

Question 6

How do correctors work?

Answer 6

Bind to immature CFTR protein, assist in protein folding, processing and trafficking to cellular membrane

Improves conformational stability within the first transmembrane domain –> decreases degradation of malformed CFTR protein in the ER

Question 7

How is the effectiveness of correctors increased?

Answer 7

Used in combination with potentiators when mutations are mixed in class, e.g. Phe508del

Elexacaftor, tezacaftor & ivacaftor (ETI) is highly effective in patients with even just one copy of p.Phe508del, regardless of the second mutation

Question 8

What are amplifiers & how do they work?

Answer 8

Increase the amount of CFTR protein that a cell makes – therefore more CFTR protein available for correctors and potentiators to work on

Stabilize mRNA to increase immature CFTR protein production - work primarily on class V mutations

Question 9

Give an example of a CFTR amplifier

Answer 9

Nesolicaftor

Question 10

What treatments are being investigated to address class 1 CFTR variants?

Answer 10

1. Read-through agents to suppress PTCs (e.g. Ataluren)
2. Engineered tRNAs insert an amino acid into the nascent polypeptide at the site of the PTC - allows translation elongation to continue in the correct reading frame and generate a full-length protein
3. Antisense oligonucleotides stabilise mRNA so it doesn’t undergo NMD

Question 11

What are the 6 classes of CFTR mutation?

Answer 11

1. Defective protein synthesis
2. Disrupted protein folding
3. CFTR channel regulation defect - reduced channel opening
4. Reduced conductance - restricted Cl- movement
5. Alternative splicing - reduced CFTR expression
6. Unstable protein - accelerated turnover at cell surface

Question 12

What systems does CF impact?

Answer 12

Pulmonary, pancreatic, gastrointestinal, reproductive

Question 13

What is the role of CFTR?

Answer 13

Chloride channel

Located in secretory epithelial cells in lungs, pancreas, intestine, vas deferens

Rate of Cl- secretion determined by no. of functional CFTR channels

Question 14

How is classical CF characterised?

Answer 14

Severe & chronic lung disease, failure to thrive, meconium ileus, pancreatic insufficiency, CBAVD

Question 15

What are the different types of non-classical CF?

Answer 15

Dysfunction in one organ system:

• bronchiecstasis
• CBAVD
• pancreatitis

Question 16

What is the significance of the intron 9 polyT and polyTG?

Answer 16

Impacts splicing efficiency of exon 10 - 90% skipped with 5T

PolyTG mediates pathogenicity of polyT (longer = disease)

Question 17

What are the common polyT/polyTG genotypes associated with?

Answer 17

5T/12TG = CBAVD

5T/13TG = atypical CF

Question 18

What is the genotype-phenotype correlation of R117H + polyT?

Answer 18

5T modifies expression of R117H in cis

R117H & 5T + classical mutation = classical CF of variable severity

R117H & 7T = variable phenotype, can be benign

R117H & 9T = benign

Question 19

What phenotype is associated with the 5T allele?

Answer 19

5T/5T or 5T + classical mutation = likely CFTR-related disease

Question 20

What class of mutation is Phe508del?

Answer 20

Class 2 - aberrant folding/ trafficking of CFTR and proteasome-mediated degradation

But also features of class 3 and 4