CFTR Gene Transfer To Lungs Of Cystic Fibrosis Patients Shows Promise

NEW YORK (Reuters Health) - Repeated adenoviral transfer of the cystic fibrosis transmembrane regulator (CFTR) gene by aerosol to the lungs of cystic fibrosis (CF) patients is well tolerated and shows signs of efficacy, according to a report in the February issue of Chest.

"This represents the first clinical evaluation of repeated aerosol dose delivery of CFTR DNA to the lower respiratory tract of patients with CF using an adeno-associated virus (AAV) vector," the authors explain.

Dr. Richard B. Moss at Stanford University in California and colleagues administered up to three monthly doses of AAV serotype 2 vector expressing CFTR (tgAAVCF) or placebo to 37 patients with mild CF (FEV1 at least 60% predicted).

Adverse events were similar in frequency and pattern between patients randomized to tgAAVCF and to placebo, the authors report, and no subject withdrew from the study because of adverse events. No events were deemed definitely related to the active treatment.

All patients randomized to tgAAVCF showed at least fourfold increases in serum neutralizing antibodies to AAV, and vector shedding was detected in most sputum samples from tgAAVCF-treated patients, the report indicates. However, these changes were not associated with adverse events or with efficacy measures.

Patients treated with tgAAVCF showed a trend in improvement of all measures of pulmonary function at day 30 (including a statistically significant improvement in FEV1 compared with placebo patients), the researchers note, but differences between groups were not statistically significant at days 60, 90, and 150 (90 days after final dosing).

Sputum IL-8 levels improved by day 14 in tgAAVCF-treated patients, the results indicate, but later levels did not differ between treatment groups.

"Gene therapy with AAV as a vector by monthly aerosol inhalation (each nominal dose is 10 trillion particles) is safe in patients with mild to moderate CF lung disease," Dr. Moss told Reuters Health. "Normal CFTR can be placed this way into bronchial epithelial cells and persists for at least one month."

Early improvements in airflow and reduction in inflammation (IL-8) in the sputum are evidence of efficacy, Dr. Moss added. "However, these findings must be replicated in more patients. Moreover, crucial questions of long-term effect, especially in light of the appearance of antibodies to the capsid, need to be answered in further studies."

Dr. Moss said that an ongoing efficacy trial of tgAAVCF at 12 centers across the United States is estimated to yield results in mid-2005.

"Other areas of gene therapy merit ongoing research, including the relative merits of various AAV serotypes, the potential role of 'helper' molecules which augment transgene expression greatly in vitro, and improvements in aerosol vector delivery systems," Dr. Moss commented.

"Eventually the role of stem cells in this as well as many other diseases offers exciting potential for a true, single-dose 'cure' since the current state of the art requires repeated dosing to 'fix' each new generation of differentiated airway cells lesioned in CF," he concluded.

Source: Chest 2004;125:509-521. [ Google search on this article ]

MeSH Headings: Genetic Techniques : Ion Channels : Membrane Glycoproteins : Membrane Proteins : Investigative Techniques : Gene Transfer : Chloride Channels : Cystic Fibrosis Transmembrane Conductance Regulator : Analytical, Diagnostic and Therapeutic Techniques and Equipment