Lecture 12 - CF - Therapies Flashcards Preview

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Flashcards in Lecture 12 - CF - Therapies Deck (40):
1

List the main therapies of CF

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

2

What are the goals of CF treatment?

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

3

Describe the physiotherapy

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

• Exercise

4

Why are antimicrobials used in CF therapy?

• Prophylaxis
• Exacerbations

5

How are antimicrobials administered in CF?

• Oral
• Intravenous
• Nebulised

6

Describe pathogen acquisition over time in patients with CF

Type of pathogen acquired depends on age

Most people will end up with Pseudomonas aeruginosa

7

How is infection controlled?

Segregation to decrease patient-patient spread

8

What are some novel respiratory therapeutics?
Give specific examples

Mucolytics
• Pulmozyme

Anti-inflammatories
• Prednisolone

9

Describe the importance of nutrition and associated therapy in CF

• 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)

10

Why is adequate growth important in CF?

Improved growth equates with improved lung function

11

Which vitamin supplements are especially important for people with CF?

Fat soluble vitamins
• A
• D
• E
• K

12

What is the treatment for pancreatic insufficiency?

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

• taken with all fat, protein & carbohydrate containing meals

13

What are some future therapies for CF?

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

14

Outline the stages of clinical trials

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

15

What is Sildenafil used for?

• Phosphodiesterase inhibitor
• it's an anti-inflammatory

16

What is KB001A?
What is its function?

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

17

What are the types of novel antibacterials?

• Dry inhaled power
• Nebulised drugs

18

Describe gene therapy of CF
What are the barriers to this therapy?

• 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

19

What is a GTA?
What are some potential GTAs?

Gene transfer agent

1. Viral GTA
• Adenovirus
• AAV

2. Non viral GTA
• Cationic liposome

20

Describe gene therapy with viral vectors

Vectors:
• Adenovirus
• Retrovirus
 • AAV

There were multiple clinical trials in the 1990's

Not efficacious

21

Describe gene therapy with non-viral vectors

Vectors:
• Liposomes containing plasmid DNA with function gene encoded

Short duration of efficacy

22

What is GL67A/ pGM169?

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

23

Describe the clinical trials of gene therapy

• 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)

24

What is trans-differentiation?

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

25

Describe stem cell treatment

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

26

Describe protein rescue therapy

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

27

What is Ivacaftor?
Describe its function

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)

28

What are the pros and cons of Ivacaftor?

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

Cons:
• very expensive

29

How was Ivacaftor identified?

High throughput screening

30

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

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

31

When was Ivacaftor FDA approved?

2012

32

What class of mutation is F508del?

Class II (defective processing of CFTR protein)

33

What is Lumacaftor?
Describe its function

• A protein rescue therapy
• A 'corrector': used for Class II mutations

Function:
• increases the amount of CFTR trafficked to the cell surface

34

Does Lumacaftor function well on its own?

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

35

What are VX-661 and VX-809?

Lumacaftor

36

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

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

37

Describe the efficacy of Lumacaftor

With Lumacaftor, CFTR expression is 15% of wild-type

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

38

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

• 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

39

What is the type of mutation in Class I?

Nonsense mutation: stop codon prevents read through of mRNA

40

What therapies are proposed for other classes of CFTR mutation?

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