Research for F508del heterozygous

Question

Hello,
I would like to know about the research for people with CF with only a single gene of this type (F508del).
Thank you in advance

Answer

Hello,

I am not aware of ongoing clinical research that specifically targets patients compound heterozygous F508del / Other-Mutation without further selection criteria for the other mutation. But many of these patients can participate in clinical trials when the expected effect of the tested treatment depends on the other mutation or doesn’t depend on the type of the mutation.
The lines of research currently in process essentially involve gene therapy and pharmacological therapy.
If gene therapy has not met all the hopes born after the discovery of the cystic fibrosis gene (CFTR gene), this line of research is however not abandoned. The therapeutic approach consists in transferring, via a vector, normal CFTR gene in the patient's cells: the expected effect therefore, theoretically, does not depends on the mutations. Results of research conducted by a British consortium are expected in late March 2015.
Pharmacological therapy is another way extremely promising: it uses new molecules to correct the malfunction of the mutated CFTR protein. This is the case of "modulators" of CFTR that include "correctors" (they are designed to enable the migration of the mutant protein to the cell membrane) and "potentiator" (they aim to improve the functioning of the mutated protein after migration in the cell membrane). These molecules target mutation classes or specific mutations, sometimes very rare because their structure and efficiency depend on the type of malfunction caused by the mutations.
These molecules (or combination of molecules) that have a significant clinical effect in patients F508del heterozygotes (carriers of a single mutation F508del) are currently the ones that act on the malfunction of the mutated protein encoded by the other mutation carried by these patients (non F508del mutation).
To date, a single molecule of this type has obtained a marketing authorization: this is Ivacaftor whose clinical efficacy has been scientifically proven in patients carrying at least one class 3 mutation ("gating" mutations). These mutations lead to the synthesis of a mutated protein that migrates well into the cell membrane but not correctly ensures its chloride channel function as the gate controlling entry into the chloride ion channel malfunctions. The marketing authorization was granted in 2012 for patients with at least one G551D mutation and, more recently, for patients with other mutation "gating". A little over a hundred patients are affected in France. Forty percent of these patients have a mutation F508del associated with a "gating" mutation and therefore can benefit from the expected effect of the molecule on the "gating" mutation.
Another international multicenter clinical study using the Ataluren molecule is currently in process for patients with at least one mutation of class 1. Approximately 10% of patients have a mutation of this class (also called "stop mutations" because they cause premature termination of the CFTR synthesis). Forty percent of these patients have F508del mutation associated with "stop mutation" and therefore can benefit from the expected effect of this molecule on the stop mutation.
In the near future, other molecules or combination of molecules will be used in clinical trials open to other compound heterozygous F508del/Other-Mutation patients as other relevant mutations are more numerous in Class 3, or 5 and partly functional. These mutations are numerous, but they are rare or very rare: the number of patients who are carriers is therefore limited. Do not hesitate to ask your CF doctor to see if you are carrying one of these mutations.
Hope this answer can help.
Sincerely.

Gilles RAULT, MD, Roscoff CF Center

13.03.2015