B30 - Future CFTR treatments

How do Potentiators work as a CF treatment?

Increase the probability the CFTR gate is open. This helps treat gating mutations

• E.g. Ivacaftor

How do Correctors work as a CF treatment?

Drugs which help correct folding, processing, trafficking and implantation into the membrane

• E.g. Lumacaftor, Tezacaftor, Elexacaftor 

Ataluren was a potential CFTR drug which was stopped in phase 3 trials.

How was Ataluren supposed to work as a treatment for Class I CF?

Ataluren targeted the premature STOP codons in Class I variants which result in a truncated protein

The hope was that Ataluren would allow the full length protein to be produced by preventing truncation.

What percentage of CF patients are eligible for a modulator?

90% of patients

Gene therapies can be ‘nebulised and inhaled’. How is this done?

Gene therapy can be placed inside a liposome

Liposome can then be inhaled and the gene therapy will be delivered to cells lining the airway

TALEN is used in gene editing. What can TALEN do which makes it useful in gene editing?

Can introduce double strand DNA breaks at precise places in the genome.

This allows genes to be targeted and fixed/replaced.

How can drugs which improve mucociliary clearance be effective in treating CF?

Drugs help clear the build up of mucus which CF causes. This prevents bacteria and harmful toxins from collecting in the mucus.

• E.g. Hypertonic saline/Dornase Alfa

SPX-101 is a failed CF drug. How did SPX-101 work?

Inhibited the Sodium channel (ENaC) in pre-clinical trials.

This showed improved mucociliary clearance in sheep model 

• Also improved airway inflammation in mouse models 

Why did the drug SPX-101 fail to get past clinical trials?

Worked in pre-clinical trials however showed no benefit to patients in clinical trials.

Denufosol is a failed CF drug. How did Denufosol work?

TMEM16A activator in pre-clinical trials.

• Calcium activated Chloride channel

Benefit to chloride transport, ciliary function and mucociliary clearance in trials.

Why did the drug Denufosol fail to get past clinical trails?

No benefits of the drug where found in clinical trials.