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Researchers discover cellular mechanisms for delivering genetic therapies

University Of Texas At Austin : 20 July, 2000  (New Product)
Researchers at The University of Texas at Austin have discovered a mechanism for targeting exact locations on strands of DNA that could greatly expand basic genetic research, open the door to new possibilities in genetic engineering and improve the ability to fight diseases, including cancer and HIV, on the genetic level.
Their research centers on mechanisms called group II introns, which they believe may be ideal for delivering therapies that could disrupt rogue genes and enhance the activity of genes that fight or prevent infection. Their discoveries will be published in the July 21 issue of the journal Science.

Dr. Alan M. Lambowitz, director of UT Austin's Institute for Cellular and Molecular Biology, and Dr. Huatao Guo, a postdoctoral researcher at the institute, are lead authors of the research. Dr. Bruce A. Sullenger, director of research for the Center for Genetic and Cellular Therapies at Duke University Medical Center, was a collaborator. Also contributing were Michael Karberg, a molecular biology graduate student at UT Austin, and Duke graduate students Meredith Long and J.P. Jones III.

The researchers at UT Austin's Institute for Cellular and Molecular Biology study gene structure, how genes are turned on and off, and the effect of genetic elements called group II introns.

Each cell holds tiny strands of deoxyribonucleic acid containing the chemical and molecular code for all genetic information. Genetic information encoded in DNA is copied into ribonucleic acid, which controls chemical activities in cells. RNA sends messages to the cells that are delivered by sequences of coded information called exons. However, between the exons are mysterious sequences whose functions scientists do not understand, called introns or junk DNA.

Group II introns are a type of intron found in laboratory organisms, bacteria and fungi. Researchers believe these particular introns may be related to ancestors of AIDS and leukemia viruses.

'We started doing very basic research in gene structure and gene evolution. We were interested in introns and how they got there,' Lambowitz said. 'We discovered that intron RNAs move and duplicate themselves, and go from one place to another, by inserting themselves directly into double stranded DNA. It was not a mechanism that anyone had ever seen before.'

Lambowitz said the researchers found that 'the mechanism by which the introns move was perfectly designed for inserting genes into specific sites, and, that the sites could actually be controlled by the researcher. There is no other vector (carrier) in which it is possible to control the site of insertion.' Lambowitz said researchers have worked for many years to aim vectors at specific targets without much success.

'People who do gene therapy use retroviruses as vectors (carriers), which are inserted randomly so there is no control over where they are going. It's a shotgun approach,' Lambowitz said. 'The intron is more like a rifle shot. You can make it go to the site of your choosing. You can knock out a gene that causes cancer or introduce a tumor-suppressor gene or target a safe site where you will not impair the function of anything else.

'This is a mechanism the group II introns evolve naturally, and we have learned how to use it and control it. It was a totally unexpected mechanism. That's the beauty of basic research.'

Introns are active in human cells, but the researchers said the mechanism has not yet been demonstrated in human chromosomes. The next step in the research would be gene therapy trials on human beings. Lambowitz said human trials are in the planning stages.

'If it all works as planned, this has pretty widespread applications in genetic engineering, in genomics for finding out the functions of particular genes, for developing anti-microbial and anti-viral therapies, and for gene therapy,' Lambowitz said. 'It's a really broad type of technology, and at least some of the applications involving bacteria are within reach now.'

As an example of how introns might work, Lambowitz cited the HIV virus. He explained that humans have a gene that is a receptor for HIV infection 'so if you could knock that out, you could prevent the entry of HIV and you could become resistant to AIDS. In the examples given in the Sciencepaper, we show you can actually target a virus like HIV or its receptor in a way that should not disrupt normal genes.'

He said the same approach could be used for herpes, for hepatitis B virus or for human papilloma virus, which is associated with cervical cancer. The approach also could be used to develop therapies for bacterial pathogens, such as those causing tuberculoses.

Lambowitz is the Mr. and Mrs. A. Frank Smith, Jr. Regents Chair in Molecular Biology and the Nancy Lee and Perry R. Bass Regents Chair in Molecular Biology. He is a professor of chemistry, biochemistry, molecular genetics and microbiology. The recipient of a National Institutes of Health Merit Award in 1993, he was elected to the American Academy of Arts and Sciences in 1995.
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