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Genetic therapy in Cystic Fibrosis

Dear expert-team,
many people are talking about exchange of genes / genetic therapy. I would be interested in the latest research; what can be done by this method so far?

Many greetings,
Dear questioner,

after discovery of mutations of the CFTR-gene causing Cystic Fibrosis in the year 1989 there had been the hope of being able within a few years to transfer the correct gene via suitable gene vehicles into the cells of the respiratory tract and therefore being able to cure Cystic Fibrosis in the most affected organ causally.

By time scientists learned why the original imagination of a CFTR gene transfer were too naive. During its developmental history our immune system has become specialized in recognizing and elinimating unknown molecules as fast as possible. Actually it has been easy to transfer the intact CFTR-gene to CF cells of the nasal mucosa, which shows a similar construction as cells of the lower respiratory tract, but unfortunately the gene was mostly inactive and the gene products were destroyed very quickly. When doing another treatment the effect was much smaller.

Research in the field of genetic therapy is done mostly in Great Britain at the moment. Two types of gene-vehicles (vectors) to treat the genetic defect in the airways of patients with CF are favoured: 1. viral vectors, 2. non-viral vectors.

1. viral vectors

It came out that the best vectors available at the moment are Lenti-viruses. After a single treatment of mice the transferred gene was detectable in the cells for an average time of 6 months. The gene is translated efficiently. In spite of the high effectiveness these vectors are at the moment only the second choice because:

a. When doing another treatment of the airways the effectiveness is low. The host has developed defending proteins and defending cells, which recognize the virus as unknown and eliminate it.

b. The viruses are integrated into the genetic material of the cell. Until now it is not possible to navigate exactly the position of the integration within the genetic material, so that non-controllable side-effects as the development of tumours may occur.

2. non-viral vectors

On the one hand non-viral vectors are less efficient compared to viruses concerning genetic transfer, but on the other hand they show multiple advantages:

- non-viral vectors can be used repeatedly for treatment without losing efficiency of the genetic therapy

- - non-viral vectors show a mechanical and thermal stability and therefore can be given as an inhalation aerosol.

- Non-viral vectors can be produced under high quality requirements of the medical drug production (so called GMP-conditions).

The consortium of genetic therapy researchers in Great Britain has been testing the efficiency of three products (PEI 25kD, GL-67 von Genzyme, DNA Nanopartikel Copernicus) in sheep and CF mice. After the results of this pre-clinical study there is a clinical study with GL-67 and a CFTR-plasmide as vector in planning. Multiple clinical investigations should identify 100 patients out of a pool of 200 adult CF-patients who are most suitable to give meaningful results in the clinical study. The first pilot study with 15 patients is done to find the right dosage. The ongoing placebo-controlled double blinded study is going to test the efficiency and security of the CFTR-gene therapy with the help of clinical investigations (inflammation locally in the lung and in general in the blood, imaging methods to document the affection of the airways, bacterial colonization of the airways etc.)

As far as I know there are no clinical studies concerning genetic therapy at the moment outside of Great Britain.

Yours sincerely

Burkhard Tümmler, Hannover