Lecture 7 - Alternative CF treatment Flashcards
Early gene therapy used…
adenoviruses
Recent gene therapy uses…
liposome complexes
First trial of non-viral CFTR gene therapy 2015 results
airway function stabilised, but not an improvement. However without a drug there is further deterioration
very diverse impact
drug is better in all parameters
Gas trapping
secondary to the obstruction of the small airways, likely to occur early in infants with CF so used as an indicator for improvement
Problem with first 2015 non-viral CFTR gene therapy
Saline control is not the best, would be better to use scrambled CFTR message but it is unethical as it cannot be guaranteed this wouldn’t have a negative effect
CFTR and ENaC autoregulation
CFTR normally inhibits ENaC
in CF, ENaC function is enhanced
SPLUNC1
naturally occurring ENaC antagonist
ENaC under normal conditions
Trypsin proteolytically cleaves ENaC which results in an increased Po therefore increasing sodium absorption
SPLUNC1 ENaC function
binds to ENaC and prevents cleavage to prevent excessive Na+ absorption
S18 peptide
Fraction of the SPLUNC1 protein, the ENaC inhibitory domain
S18 peptide function
binds to human bronchial epithelia and blocks pH-dependent binding of SPLUNC1
S18 competitive binding experiments
using fluorescent SPLUNC1
when S18 is present fluorescence is reduced because SPLUNC1 is prevented from binding, proves it binds at the same site
S18 and ASL
ASL increased, therefore showing ENaC has been inhibited
S18 and alveolar cells
Alveolar cells have both CFTR and ENaC work on reabsorption
shows ASL is increased with S18
ENaC in collecting duct principal cells
sodium renal handling can have effects on blood pressure
fewer systemic effects with S18 than amiloride as amiloride typically shows increased plasma K+ which would normally effect BP
