SCRUNCHING UP DNA into ultra-tiny balls could be the key to making gene therapy safer and more efficient. The technique is now being tested on people with cystic fibrosis.
So far, modified viruses have proved to be the most efficient way of delivering DNA to cells to make up for genetic faults. But viruses can鈥檛 be given to the same person time after time because the immune system starts attacking them. Viruses can also cause severe reactions.
As a result, researchers increasingly favour other means of delivering genes, such as encasing DNA in fatty globules called liposomes that can pass through the membranes round cells. But simply getting a gene into a cell isn鈥檛 enough鈥攆or the desired protein to be produced, you need to get the gene into the cell鈥檚 nucleus.
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At around 100 nanometres in size, most liposomes are too large to pass through the tiny pores in the nuclear membrane except when the membrane breaks down during cell division. Even if cells are rapidly dividing, delivering genes via liposomes isn鈥檛 very efficient鈥攁nd it鈥檚 no good for slowly dividing cells such as those lining the lungs.
But researchers at Case Western Reserve University and Copernicus Therapeutics, both in Cleveland, Ohio, have developed a way to pack DNA into particles 25 nanometres across, small enough to enter the nuclear pores. The nanoparticles consist of a single DNA molecule encased in positively charged peptides and are themselves delivered to cells via liposomes. In cells grown in culture, there was a 6000-fold increase in the expression of a gene packaged this way compared with unpackaged DNA in liposomes.
Trials have now begun in 12 people with cystic fibrosis, who have a faulty gene that means thick mucus accumulates in their lungs. The researchers will first test the technique on nasal cells before trying to deliver genes to the lungs.
鈥淲e鈥檙e very excited about this,鈥� says Robert Beall, president of the Cystic Fibrosis Foundation. 鈥淓verybody recognises that gene therapy could provide the cure for cystic fibrosis, and it is exciting that this is a non-viral approach.鈥�
When Pam Davis of Case Western University School of Medicine tried the technique on mice with cystic fibrosis, she found the replacement gene was expressed in nasal lining and partially restored function鈥攚ith little or no immune reaction. But that doesn鈥檛 mean the method will work in people, she warns, because mice have a very different airway structure.
Indeed, there have already been many failed attempts to treat cystic fibrosis with gene therapy. Lungs are especially challenging, says respiratory specialist Duncan Geddes of Imperial College, London, because the lung lining is designed to keep out foreign objects. The build-up of thick sputum in the lungs of cystic fibrosis patients makes the problem even worse.
But the replacement gene only needs to be expressed in a small proportion of cells, Geddes says. 鈥淚t鈥檚 extremely interesting and promising.鈥�