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ONE YEAR after locating the minute genetic fault that causes cystic
fibrosis, scientists in the US have succeeded in replacing the faulty gene
in human cells in a test tube. The altered cells functioned properly, leading
the researchers to predict that gene therapy may soon treat the disease.

‘This happened very fast,’ said James Wilson of the University of Michigan,
whose research partner, Francis Collins, helped discover the genetic defect
last year. ‘I think we are going to be surprised how quickly things are
going to happen (in gene therapy).’ The success with the cystic fibrosis
gene comes less than a week after the first gene therapy was performed on
a human, a four-year-old girl with an enzyme deficiency that cripples the
immune system (This Week, 22 September).

Wilson’s team raced to prove their method before that of another team
composed of scientists from the University of Iowa, Tufts University and
a company called Genzyme, both based in Massachusetts. Both groups succeeded
within one week of each other. Wilson’s findings appear in last week’s Cell,
and the Iowa group are publishing its results in this week’s Nature.

Cystic fibrosis is the most common inherited disease among white people
in the US, affecting about 30 000 people at any one time. It is caused by
the failure of cells in the lung, sweat glands, intestine and pancreas to
get rid of chloride ions. Normally, these leave the membrane of the cells
through ion channels. In people with cystic fibrosis, these channels are
blocked. Thick mucus which builds up in the lungs in particular, provides
a rich breeding ground for bacteria and other microorganisms. Few people
with cystic fibrosis live beyond their twenties.

Last year, Collins and Lap-Chee Tsui of the University of Toronto tracked
the cystic fibrosis defect to a gene consisting of about 250 000 base pairs,
the chemical units of DNA. The flaw was a deletion of just three of these
base pairs. As soon as the discovery was made, Wilson started trying to
replace the defective gene with a healthy one. He removed cells from the
pancreas of a person with cystic fibrosis. ‘We were dealing with the absence
of a function, so we added a complete, normal gene to the cells,’ Wilson
said. He used a retrovirus to ferry the gene into the cells. Once inside,
the normal gene began producing a protein cystic fibrosis transmembrane
regulator in the normal fashion. This opened the chloride ion channels.

The group at Iowa and Massachusetts, led by Michael Welsh, used another
virus, Vaccinia, which is commonly used to vaccinate humans against disease.
They infected cells taken from the air passages of people with cystic fibrosis
and achieved the same result as Wilson’s team. Welsh’s group reinforced
their findings by inserting a faulty gene into the same type of cells. The
chloride channels in these cells failed to open.

Work on human air passages are the route to the next step: trying the
technique directly on animals and humans. The first human experiment in
gene therapy, reported last week, used a technique known as Replacement
gene therapy. This involves removing faulty cells, adding a gene and then
replacing the cells.

This technique is not feasible with people with cystic fibrosis because
it would involve altering a large number of cells, Wilson says. His team
hopes instead to add healthy genes directly to affected cells, either using
viruses or a new complex of DNA and protein with which he is experimenting
(This Week, 11 August). People could inhale healthy genes regularly as an
aerosol spray, he suggests. Such therapies require lengthy study, Wilson
warns, but ‘this is where the research should go.’