Cystic fibrosis is a prime target for gene therapy, because just a single defective gene causes the surplus of mucus that threatens the lungs. But that same mucus has also stymied the delivery of healthy genes to lung cells. Now, researchers have found that conditioning the airways with a natural compound that thins the mucus primes cells for gene therapy.
The defective gene encodes a protein called CFTR, which channels chloride ions through cell membranes. These channels don't function properly in people with cystic fibrosis, leading to a chemical imbalance that causes cells lining the lungs to secrete too much mucus. As a result, people have problems breathing and are prone to infection.
To sneak genes into the lung cells, scientists at the Adelaide Women's and Children's Hospital in Australia turned to a natural, detergent-like component of airways that makes mucus thinner and runnier. The researchers squirted the compound, called lysophosphatidylcholine (LPC), into the nostrils of mice with cystic fibrosis. An hour later, they delivered a modified version of HIV carrying the CFTR gene. Unlike many viruses, HIV can deliver genes to nondividing cells--an important consideration in the airways, where fewer than 1% of cells are dividing at any given time.
In mice treated with LPC, the CFTR gene was still present in nasal airway cells up to 92 days later and chloride ion transport was improved for at least 110 days, the team reports in the November issue of Human Gene Therapy. In contrast, mice given the gene without LPC didn't improve. The overall improvement seems to indicate that HIV delivered the gene to many of the nondividing cells. Moreover, the length of the effect suggests that the therapeutic gene was also passed on to dividing cells--another promising sign for long-lasting treatment, says molecular biologist Donald Anson, a co-author of the study.
While the findings look promising, future studies will have to tackle the "much more challenging" problem of delivering genes to the furthest reaches of the lungs, says retrovirus researcher Andrew Lever at Addenbrooke's Hospital in Cambridge, United Kingdom.