September 01, 2010

UCLA Researchers clear hurdle on path toward gene-therapy treatment for disease

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A multidisciplinary research group at UCLA has now teamed up to not only visualize a virus but to use the results to adapt the virus so that it can deliver medication instead of disease. They constructed a model of the virus to a resolution of 3.6 angstroms (0.36 nanometers).

In a paper published last week in the journal Science, Hongrong Liu, a UCLA postdoctoral researcher in microbiology, immunology and molecular genetics, and colleagues reveal an atomically accurate structure of the adenovirus that shows the interactions among its protein networks. The work provides critical structural information for researchers around the world attempting to modify the adenovirus for use in vaccine and gene-therapy treatments for cancer.

To modify a virus for gene therapy, researchers remove its disease-causing DNA, replace it with medications and use the virus shell, which has been optimized by millions of years of evolution, as a delivery vehicle


Working in the Electron Imaging Center for Nanomachines at the CNSI (California NanoSystems Institute at UCLA), a lab run by Zhou, the researchers used cryoEM to create a 3-D reconstruction of the human adenovirus from 31,815 individual particle images.

"Because the reconstruction reveals details up to a resolution of 3.6 angstroms, we are able to build an atomic model of the entire virus, showing precisely how the viral proteins all fit together and interact," Zhou said. An angstrom is the distance between the two hydrogen atoms in a water molecule, and the entire adenovirus is about 920 angstroms in diameter.



"This breakthrough is a great leap forward, but there are still many obstacles to overcome," Wu said. "If our work is successful, this therapy could be used to treat most forms of cancer, but our initial efforts have focused on prostate and breast cancers because those are the two most common forms of cancer in men and women, respectively."

The group is working with the adenovirus because previous research has established it as a good candidate for gene therapy due to its efficiency in delivering genetic materials inside the body. The virus shell is also a safe delivery vehicle; tests have shown that the shell does not cause cancer, a problem encountered with some other virus shells. The adenovirus is relatively non-pathogenic naturally, causing only temporary respiratory illness in 5 to 10 percent of people.

CryoEM enables such a high-resolution reconstruction of biological structures because samples, in water, are imaged directly. In contrast, with X-ray crystallography (the conventional technique for atomic resolution models of biological structures), researchers grow crystal structures replicating the sample and then use diffraction to solve the crystal structure. This technique is limited because it is difficult to grow crystals for all proteins, samples for x-ray crystallography need to be very pure and uniform, and crystals of large complexes may not diffract to high resolution. These limitations resulted in critical areas of the adenovirus surface being unresolved using x-ray crystallography.


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