Lecture 12 - CF - Therapies

Question 1

List the main therapies of CF

Answer 1

• Physiotheapy
• Nutrition
• Pancreatic insufficiency treatment
• Antibiotics
• Novel therapies

Question 2

What are the goals of CF treatment?

Answer 2

• Maintenance of lung function (infections & airway clearance)
• Adequate growth
• Management of complications

Question 3

Describe the physiotherapy

Answer 3

• ACBT: active cycle of breathing techniques
• AD: autogenic drainage
• PEP: positive expiratory pressure

• Exercise

Question 4

Why are antimicrobials used in CF therapy?

Answer 4

• Prophylaxis

* Exacerbations

Question 5

How are antimicrobials administered in CF?

Answer 5

• Oral
• Intravenous
• Nebulised

Question 6

Describe pathogen acquisition over time in patients with CF

Answer 6

Type of pathogen acquired depends on age

Most people will end up with Pseudomonas aeruginosa

Question 7

How is infection controlled?

Answer 7

Segregation to decrease patient-patient spread

Question 8

What are some novel respiratory therapeutics?

Give specific examples

Answer 8

Mucolytics
• Pulmozyme

Anti-inflammatories
• Prednisolone

Question 9

Describe the importance of nutrition and associated therapy in CF

Answer 9

• close monitoring
• contact with specialist dietician
• increased intakes (120-150%) due to increased losses
• high salt, protein and salt diet
• supplemental feeds
• salt supplements
• vitamin supplements (fat soluble)

Question 10

Why is adequate growth important in CF?

Answer 10

Improved growth equates with improved lung function

Question 11

Which vitamin supplements are especially important for people with CF?

Answer 11

Fat soluble vitamins
 • A
 • D
 • E
 • K

Question 12

What is the treatment for pancreatic insufficiency?

Answer 12

• Enteric coated pancreatic enzyme microspheres
e.g. Creon
• contains lipase, protease, amylase

• taken with all fat, protein & carbohydrate containing meals

Question 13

What are some future therapies for CF?

Answer 13

• Novel inhaled antibacterials
• New anti-inflammatories
• Correction of underlying gene defect
• Protein rescue therapy

Question 14

Outline the stages of clinical trials

Answer 14

Phase I:
• low doses in healthy volunteers

Phase II:
• small cohort
• examine the effectiveness of drug

Phase III:
• large cohort
• confirm previous findings

→ To patients

Question 15

What is Sildenafil used for?

Answer 15

• Phosphodiesterase inhibitor

* it’s an anti-inflammatory

Question 16

What is KB001A?

What is its function?

Answer 16

• It’s a humanised Fab fragment
• Specific for a Pseudomonas virulence determinant
• Decreases inflammation

Question 17

What are the types of novel antibacterials?

Answer 17

• Dry inhaled power

* Nebulised drugs

Question 18

Describe gene therapy of CF

What are the barriers to this therapy?

Answer 18

• Functional version of the gene introduced to epithelial cells of the respiratory tract

Barriers:
 • the lung resilient against foreign material
→ mucociliary elevator
→ mucous layer
→ get into nucleus

Question 19

What is a GTA?

What are some potential GTAs?

Answer 19

Gene transfer agent

1. Viral GTA
   • Adenovirus
   • AAV
2. Non viral GTA
   • Cationic liposome

Question 20

Describe gene therapy with viral vectors

Answer 20

Vectors:
• Adenovirus
• Retrovirus
•AAV

There were multiple clinical trials in the 1990’s

Not efficacious

Question 21

Describe gene therapy with non-viral vectors

Answer 21

Vectors:
• Liposomes containing plasmid DNA with function gene encoded

Short duration of efficacy

Question 22

What is GL67A/ pGM169?

Answer 22

This is the cationic liposome with the DNA plasmid w/ the functional CFTR gene

Question 23

Describe the clinical trials of gene therapy

Answer 23

• 30 to date, most still in Phase I and II
• Still testing safety, not the clinical outcome

• Most have reported transient efficacy (up to 4 weeks)

Question 24

What is trans-differentiation?

Answer 24

This is when a (stem) cell can convert from one cell type to another

Question 25

Describe stem cell treatment

Answer 25

A small area of research | The results of the trials, however, have been very detrimental

Question 26

Describe protein rescue therapy

Answer 26

``` Depends on the underlying class of mutation Using drugs to overcome this dysfunctional protein ```

Question 27

What is Ivacaftor? | Describe its function

Answer 27

A protein rescue therapy • for Class III mutations (dysregulated channel, i.e. gating defect) • a 'Potentiator' Function • Ivacaftor binds the channel and allows it to function normally (i.e., keeps the channel open)

Question 28

What are the pros and cons of Ivacaftor?

Answer 28

``` Pros: • improvement in lung function • increased weight • decreased symptoms • delayed exacerbation • reduction in sweat chloride concentrations ``` Cons: • very expensive

Question 29

How was Ivacaftor identified?

Answer 29

High throughput screening

Question 30

Why is Ivacaftor so good, and why is it important?

Answer 30

It addresses the underlying defect | It is the first CF therapeutic to do so

Question 31

When was Ivacaftor FDA approved?

Answer 31

2012

Question 32

What class of mutation is F508del?

Answer 32

Class II (defective processing of CFTR protein)

Question 33

What is Lumacaftor? | Describe its function

Answer 33

* A protein rescue therapy * A 'corrector': used for Class II mutations Function: • increases the amount of CFTR trafficked to the cell surface

Question 34

Does Lumacaftor function well on its own?

Answer 34

No. This drug only gets the mutated CFTR to the surface. Need a potentiator in addition (e.g. Ivacaftor)

Question 35

What are VX-661 and VX-809?

Answer 35

Lumacaftor

Question 36

Compare the classes of mutations for which Lumacaftor, Ataluren & Ivacaftor are used

Answer 36

``` Lumacaftor: class II; F508del mutation Ivacaftor: class III Ataluren: class I ```

Question 37

Describe the efficacy of Lumacaftor

Answer 37

With Lumacaftor, CFTR expression is 15% of wild-type With Lumacaftor + Ivacaftor, CFTR expression is 30% or wild-type

Question 38

What is Ataluren? | Describe its function and efficacy seen in clinical trials.

Answer 38

* Protein rescue therapeutic * Used for Class I mutations Function: • Promotes read through of mRNA despite stop codons Efficacy: • failed to delivery improvement in FEV • except those not taking nebuliser amino glycoside

Question 39

What is the type of mutation in Class I?

Answer 39

Nonsense mutation: stop codon prevents read through of mRNA

Question 40

What therapies are proposed for other classes of CFTR mutation?

Answer 40

Ivacaftor may have efficacy in the other classes mutations (IV, V, VI)