Compound heterozygosity - does one or both defects have to be corrected causally?

Question

Hello,
my daughter, five weeks old, born with meconium ileus, genetic result: delta F 508 on one allel and a stop-mutation on the other allel, has therefore a heterozygote combination of 2 different defects.
According to my research the substance VX809 is investigated for delta F 508 and the substance PTC124 for stop-mutations. Of course there is still a long way to go for both substances to the possible availability of a drug.
My question is the following: for a causal treatment does only one of the two defects have to be corrected or does both defects have to be corrected with drugs?
Many thanks.

Answer

Hello,
theoretically, the treatment of one defect should be enough as about 4% of the population are healthy carriers of one CFTR-mutation, that means they have one functioning and one non-functioning CFTR-gene.
VX-809 is a so-called potentiator, which should make sure that more F508del-gen products come to the cell membrane and a combination with VX-770 should enhance the activity of the CFTR-ion channel.
PTC124 is a substance, which should overread the stop-codon, which is integrated to early due to the nonsense mutation, so that the entire protein is synthezised. As, however, the mutation itself is not corrected (change of the base, which changes a certain aminoacid into a stop-codon), it remains incertain, if the emerging protein is folded really correctly and/or matured and is functioning like this.
An improvement of the existing residual function is probably more promising than a restitution of a protein and its function, which is destroyed normally. But, as said, these thoughts are theoretic and only the results of many further studies will show, if and to which extent these therapeutical approaches will be sucdesful.
I hope to have answered your questions with my remarks.
Best regards,
Prof. Sabina Gallati

07.04.2011