Lecture 12 - CF - Therapies Flashcards
List the main therapies of CF
- Physiotheapy
- Nutrition
- Pancreatic insufficiency treatment
- Antibiotics
- Novel therapies
What are the goals of CF treatment?
- Maintenance of lung function (infections & airway clearance)
- Adequate growth
- Management of complications
Describe the physiotherapy
- ACBT: active cycle of breathing techniques
- AD: autogenic drainage
- PEP: positive expiratory pressure
• Exercise
Why are antimicrobials used in CF therapy?
- Prophylaxis
* Exacerbations
How are antimicrobials administered in CF?
- Oral
- Intravenous
- Nebulised
Describe pathogen acquisition over time in patients with CF
Type of pathogen acquired depends on age
Most people will end up with Pseudomonas aeruginosa
How is infection controlled?
Segregation to decrease patient-patient spread
What are some novel respiratory therapeutics?
Give specific examples
Mucolytics
• Pulmozyme
Anti-inflammatories
• Prednisolone
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)
Why is adequate growth important in CF?
Improved growth equates with improved lung function
Which vitamin supplements are especially important for people with CF?
Fat soluble vitamins • A • D • E • K
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
What are some future therapies for CF?
- Novel inhaled antibacterials
- New anti-inflammatories
- Correction of underlying gene defect
- Protein rescue therapy
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
What is Sildenafil used for?
- Phosphodiesterase inhibitor
* it’s an anti-inflammatory
What is KB001A?
What is its function?
- It’s a humanised Fab fragment
- Specific for a Pseudomonas virulence determinant
- Decreases inflammation
What are the types of novel antibacterials?
- Dry inhaled power
* Nebulised drugs
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
What is a GTA?
What are some potential GTAs?
Gene transfer agent
- Viral GTA
• Adenovirus
• AAV - Non viral GTA
• Cationic liposome
Describe gene therapy with viral vectors
Vectors:
• Adenovirus
• Retrovirus
•AAV
There were multiple clinical trials in the 1990’s
Not efficacious
Describe gene therapy with non-viral vectors
Vectors:
• Liposomes containing plasmid DNA with function gene encoded
Short duration of efficacy
What is GL67A/ pGM169?
This is the cationic liposome with the DNA plasmid w/ the functional CFTR gene
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)
What is trans-differentiation?
This is when a (stem) cell can convert from one cell type to another
Describe stem cell treatment
A small area of research
The results of the trials, however, have been very detrimental
Describe protein rescue therapy
Depends on the underlying class of mutation Using drugs to overcome this dysfunctional protein
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)
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
How was Ivacaftor identified?
High throughput screening
Why is Ivacaftor so good, and why is it important?
It addresses the underlying defect
It is the first CF therapeutic to do so
When was Ivacaftor FDA approved?
2012
What class of mutation is F508del?
Class II (defective processing of CFTR protein)
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
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)
What are VX-661 and VX-809?
Lumacaftor
Compare the classes of mutations for which Lumacaftor, Ataluren & Ivacaftor are used
Lumacaftor: class II; F508del mutation Ivacaftor: class III Ataluren: class I
Describe the efficacy of Lumacaftor
With Lumacaftor, CFTR expression is 15% of wild-type
With Lumacaftor + Ivacaftor, CFTR expression is 30% or wild-type
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
What is the type of mutation in Class I?
Nonsense mutation: stop codon prevents read through of mRNA
What therapies are proposed for other classes of CFTR mutation?
Ivacaftor may have efficacy in the other classes mutations (IV, V, VI)
