CYSTIC FIBROSIS TEST 2 QUESTIONS
WITH 100% CORRECT ANSWERS!!
What are the Goals of treatment?
Maintaining lung function
– Treat infections
– Airway clearance
Adequate growth
– Diet
– Supplementation
Managing complications, e.g.
– CFRDM
– Liver disease
Before modulators, there are symptomatic treatments. What are they?
What is the purpose of CFTR Modulators?
• Overcome basic CFTR defect
- Restore CFTR function
• Mutation (class) specific
Protein rescue therapy: Ivacaftor (Class III)
– Potentiator: compounds that increase cl- ion channel gating function of CFTR
– Class III mutation
– Gly551Asp (G551D): impairs the ability of CFTR at the cell surface to open
– Identified via high- throughput screening (HTS)
,Increase the time that activated CFTR channeled at the epithelium stays open and fucntion
This is beneficial for class III and 4
For class mutation G551D
HTS: screen hundreds of molecules at ashort time span
Describe Preclinical In Vitro Models
Cell lines
Patient-derived samples
– Primary airway cells in planar cultures
– Airway organoids
– Rectal biopsies
– Intestinal organoids
Induced pluripotent stem cells
Organ-on-a-chip system
Compounds are tested on in vitro model first
Culture patient cells on a plate and test compounds on those cells to see what impact that they
have
Organoids = grow mini organs on a plate
What is the good news for Ivacaftor (kalydeco)?
Significant improvement in lung function 10.6%
Significant ↑ in weight
Significant ↑ in time to exacerbation
Significant ↓ symptoms
Significant reduction in sweat chloride values
,First therapy to target underlying defect
Sustained benefits - short term
151 patients with G551D followed for 6 months
Sustained improvements in sweat Cl, FEV1, BMI & MCC
(not sustained anymore) benefits - longer term
96 patients with G551D followed for 5.5 y
Lung function declined over time
– Pts with lower lung function had greatest improvement
– Rate of decline higher in kids
Sustained improvements in sweat Cl, BMI and exacerbations
What is the not so good news about Ivacaftor?
Very expensive
Protein rescue therapy: Class II mutations
Most common mutation
– Phe508del (ΔF508)
• Correctors
– ↑ cellular processing and delivery of CFTR proteins to cell surface
– small molecular compounds
• VX-809 (Lumacaftor) VX-661 (Tezacaftor) & VX-445 (Elexacaftor)
– Once trafficked to cell surface, Phe508del– CFTR doesn’t function optimally
• Combine with potentiator, Ivacaftor
-> require more than just a potentiator (protein is misfolded and gets destroyed across the cell)
Leads to development of compounds contain more than one molecule
, 1. lumacaftor-ivacaftor (Orkambi)
2. Tezacaftor + ivacaftor (Symdeko)
lumacaftor-ivacaftor (Orkambi)
• Homozygous for phe508del
• Listed on PBS from 12 months of age
• Mean change in FEV1 of 2.6 to 4.0%
• Exacerbation rate ↓ 39% • ↑weight:1.23to1.57kg
2 copies of F508del
Frequency of exacerbation decrease
Approved and bcm available in australia
Somewhat effective
Tezacaftor + ivacaftor (Symdeko)
Heterozygous for phe508del/residual function mutation
Mean change in FEV1 6.8%
↓ sweat Cl 9.5mmol/L
no change in BMI or PEs
Homozygous for phe508del
Mean change in FEV1 4% Exacerbation rate ↓ 35% no change in BMI
Hetero: Mutations that have some residual function of CFTR – milder mutation
Homo: No reduction in sweat chloride
Symdeko
Listed on PBS from Dec 2019
– Patients > 12 years
WITH 100% CORRECT ANSWERS!!
What are the Goals of treatment?
Maintaining lung function
– Treat infections
– Airway clearance
Adequate growth
– Diet
– Supplementation
Managing complications, e.g.
– CFRDM
– Liver disease
Before modulators, there are symptomatic treatments. What are they?
What is the purpose of CFTR Modulators?
• Overcome basic CFTR defect
- Restore CFTR function
• Mutation (class) specific
Protein rescue therapy: Ivacaftor (Class III)
– Potentiator: compounds that increase cl- ion channel gating function of CFTR
– Class III mutation
– Gly551Asp (G551D): impairs the ability of CFTR at the cell surface to open
– Identified via high- throughput screening (HTS)
,Increase the time that activated CFTR channeled at the epithelium stays open and fucntion
This is beneficial for class III and 4
For class mutation G551D
HTS: screen hundreds of molecules at ashort time span
Describe Preclinical In Vitro Models
Cell lines
Patient-derived samples
– Primary airway cells in planar cultures
– Airway organoids
– Rectal biopsies
– Intestinal organoids
Induced pluripotent stem cells
Organ-on-a-chip system
Compounds are tested on in vitro model first
Culture patient cells on a plate and test compounds on those cells to see what impact that they
have
Organoids = grow mini organs on a plate
What is the good news for Ivacaftor (kalydeco)?
Significant improvement in lung function 10.6%
Significant ↑ in weight
Significant ↑ in time to exacerbation
Significant ↓ symptoms
Significant reduction in sweat chloride values
,First therapy to target underlying defect
Sustained benefits - short term
151 patients with G551D followed for 6 months
Sustained improvements in sweat Cl, FEV1, BMI & MCC
(not sustained anymore) benefits - longer term
96 patients with G551D followed for 5.5 y
Lung function declined over time
– Pts with lower lung function had greatest improvement
– Rate of decline higher in kids
Sustained improvements in sweat Cl, BMI and exacerbations
What is the not so good news about Ivacaftor?
Very expensive
Protein rescue therapy: Class II mutations
Most common mutation
– Phe508del (ΔF508)
• Correctors
– ↑ cellular processing and delivery of CFTR proteins to cell surface
– small molecular compounds
• VX-809 (Lumacaftor) VX-661 (Tezacaftor) & VX-445 (Elexacaftor)
– Once trafficked to cell surface, Phe508del– CFTR doesn’t function optimally
• Combine with potentiator, Ivacaftor
-> require more than just a potentiator (protein is misfolded and gets destroyed across the cell)
Leads to development of compounds contain more than one molecule
, 1. lumacaftor-ivacaftor (Orkambi)
2. Tezacaftor + ivacaftor (Symdeko)
lumacaftor-ivacaftor (Orkambi)
• Homozygous for phe508del
• Listed on PBS from 12 months of age
• Mean change in FEV1 of 2.6 to 4.0%
• Exacerbation rate ↓ 39% • ↑weight:1.23to1.57kg
2 copies of F508del
Frequency of exacerbation decrease
Approved and bcm available in australia
Somewhat effective
Tezacaftor + ivacaftor (Symdeko)
Heterozygous for phe508del/residual function mutation
Mean change in FEV1 6.8%
↓ sweat Cl 9.5mmol/L
no change in BMI or PEs
Homozygous for phe508del
Mean change in FEV1 4% Exacerbation rate ↓ 35% no change in BMI
Hetero: Mutations that have some residual function of CFTR – milder mutation
Homo: No reduction in sweat chloride
Symdeko
Listed on PBS from Dec 2019
– Patients > 12 years
