VX 770 without effect

Question

Hello,

after taking VX770 for four weeks, I (29 years old, FEV 32%) could not detect any measurable or subjective improvement (FEV unchanged and large amount of secretion as usual).

Since, apart from having the G551D mutation, I am also G542X carrier, the question is whether this second mutation could possibly "prevail" and thus explain the lack of effectiveness of VX770.

If not, do you happen to have any idea what could be the reason for this "standstill"?

Many thanks for your answer.

Answer

Dear questioner,

the G551D and G542X mutations translate as follows:

At position 551 on one of the two CFTR genes you are carrying, there is amino acid D (aspartic acid) instead of G (glycine). The drug VX770 is targeted at this error, since the CFTR protein with the D at position 551 is less active than the unchanged CFTR protein with the G551. VX770 manages to correct the activity of the D551 protein partially, and this is supposed to help you as well, of course. At position 542 on the other CFTR gene, on the other hand, a stop codon (X) instead of the amino acid G is read; as a result, no other protein building blocks can be inserted at this position. The cell notices that position 542 is much too early for a stop signal – and reacts by decomposing the corresponding carrier RNA. Due to this mechanism (called nonsense-mediated decay), the information of the CFTR with the X at position 542 is hardly put into effect at all in the cells. In other words: the G542X mutation cannot be the cause of the standstill – there is no corresponding shortened CFTR protein.

Please do tell your treating doctor about your impression that the VX770 is apparently not helping – perhaps there is another explanation.

Kind regards
Dr. Frauke Stanke

30.07.2012