Adeno-Associated Virus Is Safe Vector for Cystic Fibrosis Gene Therapy

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Adeno-Associated Virus Is Safe Vector for Cystic Fibrosis Gene Therapy

By Karla GaleNEW YORK (Reuters Health) Jul 24 - Phase I trial results suggest

that recombinant adeno-associated serotype 2-based vectors (rAAV2) are safe

for cystic fibrosis (CF) gene therapy, according to a report in the July 20th

issue of Human Gene Therapy.Dr. Terence R. Flotte, of the University of

Florida, Gainesville, and colleagues, report their findings from the first human

trial of rAAV2 expressing full-length human cystic fibrosis transmembrane

conductance regulator (tgAAVCF). Subjects were 25 volunteers, ages 15 to 43,

with

mild-to-moderate lung disease and at least one known disease-causing CFTR mutant

allele. " The intent was to establish safety and see if we were working through a

dose range with reasonably good transfer efficiency, " Dr. Flotte told Reuters

Health. " Clearly, there was no indication of toxicity. " That finding is

extremely important, he explained, since other viral vectors have been

associated

with significant inflammatory responses or other major toxicities.The vector

was administered to one side of the nose and to a single bronchopulmonary

segment of the right lower lobe. Antibiotic treatment was initiated 4 days prior

to

vector administration and continued until 14 days afterward.Adverse events

were common. Only one subject, however, experienced a severe adverse event

considered to be possibly related to the vector. And even in that case, the

episode

was similar to three previous events that occurred in the 3 months prior to

study entry. One subject exhibited transient shedding of vector in sputum, but

otherwise there was no viral shedding in urine, stool or sputum.Gene transfer

was documented in 6 subjects receiving the highest doses (more than 10 million

replicating units).The researchers observed no physiologic effect as measured

by nasal transepithelial potential difference, which Dr. Flotte described as a

" back-up test commonly used after the sweat test and genotyping in diagnosing

CF. " It could be that similar testing performed in the lower airways would

show more evidence, but such testing is technically difficult, he said. But

trials conducted by other groups suggest at least short-term clinical benefit,

he

added.Dr. Flotte noted that his group's findings support continued development

of tgAAVCF for gene transfer. In fact, he pointed out, the rAAVR2 vector " will

probably work even better in other types of tissue, such as skeletal muscle,

the retina and the brain " for delivering gene therapy.His group is currently

enrolling up to 200 CF patients at 11 sites for a randomized, control trial, in

which tgAAVCF will be administered as an aerosol.Hum Gene Ther 2003;14:00-00.

Becki

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