Gene therapy hope for cystic fibrosis

[Guest guest]

SMaRT treatment for fatal disease shows promise.

4 January 2002

JEREMY THOMSON

 

A new form of gene therapy that fools the body into repairing the faulty

gene in cystic fibrosis sufferers is looking promising in the lab.

 

Xiaoming Liu and colleagues at the University of Iowa, Iowa City, used a

technique dubbed 'SMaRT' to sneak a decoy genetic sequence into diseased

human lung cells grafted into a living mouse. The cells' function was

boosted by 10 per cent - enough to keep the disease under control1.

 

Cystic fibrosis, the most common life-threatening genetic illness in Europe

and the United States, prevents salts from moving through body tissues

properly, disrupting digestion and more importantly leading to chronic lung

infection. Despite great advances in treatments, many patients do not reach

adulthood and no cure is available.

 

For the past decade researchers have had little success treating cystic

fibrosis with conventional gene therapy, in which a complete corrected gene

is simply added to the patient's DNA. SMaRT works differently. It

interferes with the processing of RNA - the intermediate stage between DNA

and the proteins that make up body tissue.

 

When the body constructs a new protein, it first copies the relevant DNA

sequence into a blueprint RNA strand. Mammals' DNA contains long stretches

of 'junk', copies of which must be removed from RNA before the final

protein can be built. So a cellular machine called the ribosome snips the

RNA strand into pieces, discards the junk and stitches it together again.

 

Liu's team take advantage of the ribosome's tidying to sneak in a new RNA

fragment. As the ribosome pastes the snipped-up RNA chunks back together,

it incorporates the new sequence, which corrects the error that causes

cystic fibrosis in the cell.

 

The researchers engineered a virus to infect lung cells and implant the

fragment - called a 'minigene' - into their DNA. As it is read at the same

time as the faulty cystic fibrosis gene, the minigene is always present in

the cell when the ribosome is doing its cutting and pasting.

 

Because the technique acts at the intermediate RNA stage, the cell still

regulates the expression of the gene. This ensures that the right amount of

protein is produced in the right places - a big advantage over conventional

gene therapy.

 

Despite its promise, the technology has a long way to go before it reaches

the clinic. The viruses that deliver the minigene are not very efficient,

and the body's immune system soon destroys them.

 

Another problem is persuading the cell to keep using the new minigene.

 

" Fooling Mother Nature is not easy, " says Ronald Crystal, a gene-therapy

expert at Cornell University in Ithaca, New York. " The central dogma of a

gene begetting the protein it encodes is something that the cell defends

with a vengeance. "

 

References 1. Liu, X. et al. Partial correction of endogenous F508 CFTR in

human cystic fibrosis airway epithelia by spliceosome-mediated RNA

trans-splicing. Nature Biotechnology, 20, 47 - 52, (2002).

© Nature News Service / Macmillan Magazines Ltd 2002

 

 

 

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