PLANS for using HIV and related viruses to overcome a major hurdle in gene therapy have been dealt a blow. Unlike most of the vectors used in gene therapy, HIV and other 鈥渓entiviruses鈥� should be able to deliver genes to cells that aren鈥檛 dividing. But the latest research shows that they don鈥檛 always do so.
Many gene therapy trials have yielded disappointing results, mainly because so few cells in the target tissue take up the therapeutic gene. At any one time, the vast majority of our cells aren鈥檛 dividing. So finding a vector that can carry genes into these cells should help overcome this problem鈥攁nd several experiments with lentiviruses have suggested that they just might do the job.
Following early successes, several groups are now planning to use HIV, stripped of the genes that make it so deadly, for gene therapy against AIDS (New 杏吧原创, 6 February 1999, p 5). And other research teams are experimenting with similarly genetically disabled lentiviruses, such as equine infectious anaemia virus, for a wide range of gene therapies.
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But Mark Kay, Frank Park and their colleagues at the Stanford University School of Medicine in California have now shown that lentiviruses can fail to deliver. They loaded harmless variants of HIV with a marker gene and injected them into mice through the vein from the gut that enters the liver. When the researchers later examined the organs, they found that the gene was only taken up by those rare liver cells that were dividing or were in the process of copying their DNA鈥攁 necessary prelude to cell division.
Worse still, Kay and his colleagues found that when the lentiviruses were given in higher doses, they appeared to cause liver damage. Large amounts of the enzyme alanine aminotransferase, which is released by damaged liver cells, showed up in the animals鈥� bloodstreams.
The results are bad news for gene therapists who are backing the lentivirus approach, as the liver is the main target for attempts to introduce genes to correct a wide variety of metabolic disorders. But lentivirus enthusiasts say that results in other tissues are still looking good.
鈥淭he liver is only one target organ,鈥� says Sue Kingsman, scientific director of Oxford BioMedica, a British company developing lentiviral gene therapies to fight cancer. 鈥淲e鈥檝e done a lot of work with lentiviruses in the mouse brain, and they鈥檝e been fantastic, with high doses and no signs of toxicity,鈥� she says.
Experiments with human cell cultures are also yielding encouraging results, says Kingsman. 鈥淲ith the equine virus, time and time again we get good transfer in human cells that don鈥檛 divide.鈥�
鈥淚t鈥檚 not the end of the line,鈥� agrees Kay, 鈥渂ut it narrows the applications to some degree. Lentiviruses may not be as broadly useful as originally thought.鈥�