Future of gene therapy in CF

Question

Hello.
We don’t hear much talk any more about gene therapy and this treatment seems outdated ...
Can you tell me a little more: what are the tracks to come in this area? Are there special difficulties to operate this way? Is this therapy still a hope for patients with cystic fibrosis?
Thank you for answering to me.
Sincerely.

Answer

Hello,
Gene therapy can be defined schematically as treatment with DNA genes which introduced the concept of "gene-drug."
Developing such a treatment requires a successful research program called "translational". These programs require the cooperation of teams with different but complementary expertise to complete all the steps that separate the basic knowledge from the effective treatment of the patient.
First, it is important to know the gene responsible for the disease, not only to have localized it (on the short arm of chromosome 7, regarding the CFTR gene for cystic fibrosis), to have analyzed its chemical composition, to have cloned it (reproduced identically in the laboratory) but also to have understood the mechanisms that govern its operation within the cell.
A feature of gene therapy is the need for vectors capable of carrying the gene-drug for introduction into the target cell, to reach the cell nucleus, insert it into the genome of the individual so that, without disturbing the operation of other genes, it can initiate any steps for the synthesis of the CFTR protein, its migration into the cell membrane and the restoration of normal operation of the channel controlling transport of chloride.
The discovery of the CFTR gene in 1989 opened the prospects of gene therapy for cystic fibrosis, enthused research teams who have undertaken in the years 1990/2000, many works. To date, this work has not yet exceeded the Phase 2 clinical trials.
The problems to be solved are schematically related to vectors and its "target."
Regarding vectors, different problems depending on whether viral vectors or synthetic vectors:
• Viruses have the potential to use their natural ability to enter (infect) the cells of the body to integrate the DNA of its host (the patient in this case) and make him make the DNA regulated by its own protein. Used for therapeutic purposes, the virus must be modified, firstly to remove or reduce its pathogenic infectious effect, secondly to integrate its DNA into a normal CFTR gene that will compensate for the defect in the CFTR gene mutated in the host. The Phase 1 trials have concluded that the effectiveness but also the poor tolerability of viral vectors can certainly sustainably correct a malfunctioning CFTR at the cost of significant side effects associated with inflammation they cause.
• The synthetic vectors, in contrast, were much better tolerated but failed to demonstrate sufficient efficacy or durable enough.
• Regarding the treatment target, the problems are due to the fact that the stem cells of the lung are not well known today and the pulmonary epithelium in cystic fibrosis is redesigned leading to efficient gene transfer into very inefficient lung cells.
Today, conclusion of researchers and doctors is that we must return to a more basic research to develop more effective and less toxic vectors before resuming testing in humans.
A test is currently led by an English consortium. These researchers do not use viral vectors but chemical synthezised vectors to introduce the CFTR gene in the lungs of patients. We'll probably have the results of this Phase 2 trial in 2014.
To conclude, the gene therapy for cystic fibrosis is not set aside: it is not totally excluded that the progress in basic research is permitting in a few years to return to test patients. But it is not on the agenda now.
Hoping to have given the clearest possible answer to your question.

Dr. Gilles Rault with the special contribution of Professor Claude FEREC

03.05.2013