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BIOM30002 - M2M > Lecture 12 - CF - Therapies > Flashcards

Lecture 12 - CF - Therapies Flashcards

1
Q

List the main therapies of CF

A
  • Physiotheapy
  • Nutrition
  • Pancreatic insufficiency treatment
  • Antibiotics
  • Novel therapies
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2
Q

What are the goals of CF treatment?

A
  • Maintenance of lung function (infections & airway clearance)
  • Adequate growth
  • Management of complications
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3
Q

Describe the physiotherapy

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

• Exercise

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4
Q

Why are antimicrobials used in CF therapy?

A
  • Prophylaxis

* Exacerbations

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5
Q

How are antimicrobials administered in CF?

A
  • Oral
  • Intravenous
  • Nebulised
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6
Q

Describe pathogen acquisition over time in patients with CF

A

Type of pathogen acquired depends on age

Most people will end up with Pseudomonas aeruginosa

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7
Q

How is infection controlled?

A

Segregation to decrease patient-patient spread

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8
Q

What are some novel respiratory therapeutics?

Give specific examples

A

Mucolytics
• Pulmozyme

Anti-inflammatories
• Prednisolone

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9
Q

Describe the importance of nutrition and associated therapy in CF

A
  • 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)
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10
Q

Why is adequate growth important in CF?

A

Improved growth equates with improved lung function

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11
Q

Which vitamin supplements are especially important for people with CF?

A 
Fat soluble vitamins
 • A
 • D
 • E
 • K
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12
Q

What is the treatment for pancreatic insufficiency?

A

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

• taken with all fat, protein & carbohydrate containing meals

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13
Q

What are some future therapies for CF?

A
  • Novel inhaled antibacterials
  • New anti-inflammatories
  • Correction of underlying gene defect
  • Protein rescue therapy
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14
Q

Outline the stages of clinical trials

A

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

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15
Q

What is Sildenafil used for?

A
  • Phosphodiesterase inhibitor

* it’s an anti-inflammatory

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16
Q

What is KB001A?

What is its function?

A
  • It’s a humanised Fab fragment
  • Specific for a Pseudomonas virulence determinant
  • Decreases inflammation
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17
Q

What are the types of novel antibacterials?

A
  • Dry inhaled power

* Nebulised drugs

18
Q

Describe gene therapy of CF

What are the barriers to this therapy?

A

• 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
Q

What is a GTA?

What are some potential GTAs?

A

Gene transfer agent

  1. Viral GTA
    • Adenovirus
    • AAV
  2. Non viral GTA
    • Cationic liposome
20
Q

Describe gene therapy with viral vectors

A

Vectors:
• Adenovirus
• Retrovirus
•AAV

There were multiple clinical trials in the 1990’s

Not efficacious

21
Q

Describe gene therapy with non-viral vectors

A

Vectors:
• Liposomes containing plasmid DNA with function gene encoded

Short duration of efficacy

22
Q

What is GL67A/ pGM169?

A

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

23
Q

Describe the clinical trials of gene therapy

A
  • 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
Q

What is trans-differentiation?

A

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

25
Q

Describe stem cell treatment

A

A small area of research

The results of the trials, however, have been very detrimental

26
Q

Describe protein rescue therapy

A 
Depends on the underlying class of mutation
Using drugs to overcome this dysfunctional protein
27
Q

What is Ivacaftor?

Describe its function

A

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
Q

What are the pros and cons of Ivacaftor?

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

Cons:
• very expensive

29
Q

How was Ivacaftor identified?

A

High throughput screening

30
Q

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

A

It addresses the underlying defect

It is the first CF therapeutic to do so

31
Q

When was Ivacaftor FDA approved?

A

2012

32
Q

What class of mutation is F508del?

A

Class II (defective processing of CFTR protein)

33
Q

What is Lumacaftor?

Describe its function

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

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

34
Q

Does Lumacaftor function well on its own?

A

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

35
Q

What are VX-661 and VX-809?

A

Lumacaftor

36
Q

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

A 
Lumacaftor: class II; F508del mutation
Ivacaftor: class III
Ataluren: class I
37
Q

Describe the efficacy of Lumacaftor

A

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

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

38
Q

What is Ataluren?

Describe its function and efficacy seen in clinical trials.

A
  • 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
Q

What is the type of mutation in Class I?

A

Nonsense mutation: stop codon prevents read through of mRNA

40
Q

What therapies are proposed for other classes of CFTR mutation?

A

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

BIOM30002 - M2M (36 decks)

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