Ongoing Research: GENE THERAPY RESEARCH

Because cystic fibrosis is a genetic disease, adding a normal CFTR gene to affected cells could correct the problems in cystic fibrosis. This is called gene therapy. In studies of laboratory tissue culture and animals, we have successfully inserted a normal CFTR gene into airway cells. We used the DNA from the normal CFTR gene. Adenovirus gene therapy is being conducted in our clinical trials. The virus is commonly found in human airways and can cause a "cold". It has been altered so it cannot reproduce normally. These changes limit its ability to cause disease, to grow, and to spread.

We have so far conducted two clinical trials in humans using recombinant adenovirus vectors. These studies have shown that adenovirus vectors encoding CFTR can express the trasnsgene in airway epithelia and can at least partially correct the CF defect in electrolyte transport. However, there are several limitations to adenovirus mediated gene transfer. First, the efficiency of gene transfer to uninjured airway epithelia is low. Second, because gene transfer to airway epithelia is transient, the use of recombinant adenovirus vectors will require repeat administration. The requirement for repeat administration is a concern because administration of high doses of adenovirus can generate neutralizing antibodies which can limit subsequent gene transfer. Furthermore, administration of high doses of adenovirus vectors can generate an inflammatory response. Additionally, we are using a lipid (a fat-like molecule) to combine the DNA and carry it into cells. Our results from this study indicate the nonviral vectors can transfer CFTR cDNA to airway epithelia and at least partially restore the Cl- transport defect characteristic of CF, however it seems likely that improvement in the overall efficacy of gene transfer are required for a robust treatment for CF. Correction achieved with DNA alone in this study suggested that plasmid-mediated gene transfer might be a future option in CF. The ultimate purpose of this research is to find a better treatment for cystic fibrosis. In these studies, we examine the safety and possiblity of correcting the basic defect by applying a normal CFTR gene onto the cells of the nasal mucosa in people who have cystic fibrosis.

Current Studies: The first goal of these studies is to evaluate the safety of gene transfer in the nasal epithelia of cystic fibrosis (CF) patients. The second goal is to evaluate the ability of an adenovirus and/or cationic lipid to enhance gene transfer to airway epithelia in vivo, and to correct the biochemical defect seen in CF people. The third goal is to evaluate the ability of plasmid DNA alone to correct the electrophysiologic properties of the nasal epithelium in CF patients.

To see individual studies visit the pages of Joseph Zabner.

If you would like to participate in our gene transfer studies please contact Jan Launspach, RN.
Adenovirus mediated gene transfer to nasal epithelia
Cationic lipid mediated gene transfer nasal epithelia