Chapter 11, Problem 35P

The drug ivacaftor has recently been developed to treat cystic fibrosis in children with the rare G551D mutant allele of CFTR.

a.	Do you think that ivacaftor would be effective only in patients homozygous for the G551D mutation, or might it work as well in compound heterozygotes in which one copy of chromosome 7 had G551D and the other copy a different allele of CFTR, such as the more prevalent allele ΔF508? (The protein encoded by G551D folds up properly and inserts into the cell membrane, but is inefficient in chloride ion transport. Ivacaftor increases the efficiency of G551D’s ion transport. The ΔF508 protein does not fold up properly and therefore does not get inserted into the cell membrane.)
b.	Why do you think ivacaftor would be more effective in children than in older cystic fibrosis patients?
c.	The scientists who developed ivacaftor had a model for cystic fibrosis: a line of cells that grow in culture and that are homozygous for G551D. These cells accumulate mucus at their surfaces that prevent cilia (tiny hairs on the outside of cells) from beating. Explain how the scientists could use this disease model to screen for drugs that would be effective against G551D-associated cystic fibrosis.
d.	Ivacaftor is used in combination with an even newer drug called lumacaftor to treat individuals homozygous for the most common CF allele, ΔF508. Lumacaftor helps the ΔF508 mutant CFTR protein fold properly so that it can insert in the cell membrane. Why do you think that neither lumacaftor nor ivacaftor alone are effective in treating ΔF508 homozygotes, while the combination of both drugs is effective?