Possible medicamentous treatment of this form of mutation?

Question

Dear expert team,

I have already asked a question about the respective CF mutation form of my son; many thanks for the extensive answer (see below).

Now, I would also like to know if there will be a medicamentous treatment for my son’s mutation form in the near future?

Best regards,
N.R.
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The following question was asked by me in May [2013].

Forms of mutations

Question:
My son has been diagnosed to suffer from CF additionally due to a meconium ileus and at the same time a pathological result of the newborn screening and a subsequent sweat test.
After a detailed analysis of the genetic testing we got the result of the kind of mutation: DF508/del.13/14a.

As I have read that the forms of mutations are divided into 5 classes according to severity, I would like to know now, if in case of this kind of mutation still functioning proteins are produced in the cell (class 5) respectively if it is a class 2 mutation, i.e. the protein is not able to mature in den endoplasmatic reticulum.

Is there an influence on the severity of the course of CF due to a heterozygous respectively a homozygous form of the mutation?
Best regards,
N. R.

Answer
Dear N. R.

I answer your question in 3 parts:

first of all I will address the 2 mutations, then the connection between the severity and the homozygous forms of mutations.

1. CF-mutation F508del
In case of F508del, it is a classical CF-mutation of type II. The mutation is well known: 70% of CF-genes carry this mutation, 50% of CF-patients are homozygous for this mutation. F508del is a class 2 mutation.

2. CF-mutation "del.13/14a"

Now to "del.13/14a": presumably its a matter of a deletion (therefore del) of a great part of the CF-gene (presumably exon 13 and 14a, therefore "13/14a"). I write "presumably" as the name "del.13/14a" cannot be found either in the international CF-gene mutation database (there are at the moment at least nearly 2000 variants of the CF-gene listed there) nor it is an official mutation name (del13/14a is a colloquial description, for deletions there are unfortunately no easily understandable international valid rules of name-giving). I would not like to guess here: please try to contact the human genetic specialist in charge, that first of all it is doubtlessly clear, if in your son indeed the exons 13 and 14a of the CFTR-gene are deleted. In case this tradition pertains, "del13/14a" is a so-called "out-of-frame-deletion", as a consequence a mutation class 1, from which no functional protein can derive.

3. Grade of severity and mutation combination
In general a mutation genotype "class 1/ class 2" leads to a typical CF, that e.g. is always accompanied by pancreatic insufficiency. Furthermore however, the following is true: dependent on the inherited mutations one can draw conclusions on the average course of the illness in a group of patients with the same CFTR-mutations, however the validity for the individual course of a single patient is NOT given thereby. In a recent statement of an internationally composed CF-expert group it says word for word: "...broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not acurately predict individual outcome. The use of CFTR-genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended...."(for the sake of completeness the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The reasons for this lack of predictive value for the single human being are all influence factors on the course of CF, that play a role besides the CFTR-mutation genotype (environmental factors, other inherited factors, especially important: physician and therapeutic management of the illness) - according to the recent estimate these "non-CFTR-factors" have a greater significance as the sole CFTR-mutation genotype.

Best regards,
Frauke Stanke
18.06.2013

Answer

Dear questioner

For the genomical deletion del13./14a there will be most probably no specific therapy – but the works for a therapy for the mutation F508del (alias DF508) are in good progress.

For your situation it is important to know that no functioning CFTR-protein can be built from the gene with the dysfunction del13./14a, so that your son looks - from the perspective of a cell biologist, molecular biologist or molecular physician - like a homozygous carrier of the mutation F508del and most probably can also be treated with the newest medication for it.

The current status of molecular therapeutics for F508del-CFTR can be summarized as follows (I cite an information given by the Muko e.V. in the internet) [“Muko e.V.” is the German patient organisation; the information given under the following link is in German and was translated into English by ECORN-CF; it is not an official translation]:

“Should the approval studies with the combination of VX-809 and Ivacaftor be successful and confirm the first positive results regarding effectiveness and safety, a new medicament for the treatment of CF patients with two F508del mutations could be available in a few years. However, it is difficult to know in advance if this will work because a clinical development can still fail in a very advanced stage of development. The new potential medicaments surely do have a high potential but one has to wait for the study results to come before it can be judged if and how much they can help CF individuals.“

This is the link to the complete [German] text:
muko.info/forschung/news-detail-und-archiv/detailansicht/article/zulassungsprogramm-fuer-korrektur-des-f508del-soll-2013-starten/17.html


Summarizing: The therapy for F508del-CFTR is currently being proven. There are promising findings so that an admission procedure is persued. However, there is no medicament so far that can be bought in the pharmacy.

Best regards,
Frauke Stanke

31.07.2013