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Detector technology aids in development of cystic fibrosis therapy

Imaging device pinpoints transferred gene



As the radioactive element decays, it releases energy in the form of gamma radiation photons. Photons emitted in the direction of the detection system pass through a collimator (essentially a slab of lead with very small, parallel holes in it), which lets only those photons with paths that are parallel with the holes through, making it possible to calculate the paths of the photons. Once through the collimator, photons strike a sodium iodide scintillation crystal. The crystal absorbs the gamma radiation photons and converts them into light photons that can be detected by a photomultiplier tube. Exiting the crystal, the light photons enter a position sensitive photomultiplier tube, where the light signals are detected, amplified and converted into electrical pulses. The pulses are then digitized and sent to a computer where sophisticated software translates the digital signal into an image. (JLab graphic)
Click here for a high resolution photograph.

More than 10 million people in the United States carry the defective gene responsible for cystic fibrosis, a debilitating disease that affects about 30,000 Americans. There is no cure for the disease; treatments focus on relieving the symptoms and preventing life-threatening infections. But studies in mice with a new imaging technique perfected by Jefferson Lab's Detector Group suggest that researchers at Case Western Reserve University may have found a way to replace the gene that causes cystic fibrosis.

Cystic fibrosis is a good target for gene therapy. The disease is caused by a defect in a single gene, which scientists refer to as CFTR. What's more, a therapeutic CFTR gene, a synthetic copy of a working human CFTR gene, is already available. But researchers are leery of using conventional gene therapy to deliver the therapeutic CFTR gene to patients.

In conventional gene therapy, a virus is used to deliver a therapeutic gene to target cells. But this method may not be viable for cystic fibrosis patients, who are already battling chronic lung infections and inflammation. "If we deliver a virus to the lungs, even if it's a hollow virus, it will initiate an inflammatory response, making the patient even sicker. So that's the last thing we need in the cystic fibrosis patient," explains Zhenghong Lee, a researcher with Case Western Reserve University and University Hospitals of Cleveland.

In research with mice at his home institution, Lee and colleagues Assem Ziady and Pamela Davis are looking for a different mode of delivery. In a previous study, they found that dripping a solution containing the CFTR gene into the noses of mice could successfully deliver the gene into the lungs. But successful gene therapy depends not only on delivery of the gene, but also on good gene transfer -- the ability of cells in the body to take and express the new gene as one of their own.

To test how well the gene is transferred with the inhalation delivery method, Lee and his colleagues repeated the experiment with a gene often used to measure successful transfer. A day later, the experimenters injected a radioactive tracer and acquired x-ray and gamma images of the mice with Jefferson Lab's custom-built small animal imager -- a planar gamma scintigraphy device with an adjunct small commercial x-ray detector. The study revealed that the mice cells were expressing the new gene in the lungs. It also showed that JLab's small animal imaging system is capable of imaging gene functionality in living animals.

Lee says the next step is to continue improving Jefferson Lab's small animal imager to get an even clearer picture of gene function after gene therapy. "We want to introduce a third imaging modality, bioluminescence, which can be measured with an optical camera. These imaging methods will be independent and cross-check each other," Lee says.

Drew Weisenberger, JLab principal investigator on the project, agrees, "I think a tri-modal imaging device has the potential to bring a very powerful tool to biomedical research. The first modality, x-ray, tells you about structure. The other two modalities, gamma emission and optical, can both give you information on function, allowing doctors to measure two different functions at the same time," he explains.

Stan Majewski, Detector Group leader, is also intrigued by the prospect of building a tri-modal imaging system; he originally proposed adding the third imaging modality to the system for this and other Detector Group projects. "We're talking about building the first tri-modality imager. And the more I hear about the optical part, the more excited I get about meeting the challenge," he says.

Lee says he wants to further develop and test the inhalation gene therapy technique to prove its safety and effectiveness in small animals. Eventually, he wants to use a therapeutic CFTR gene with the therapy technique in patients. "Right now, cystic fibrosis is a fatal disease. But if everything works out, and we can make it a manageable disease, I think that would be really, really good," Lee says.

The Detector Group has designed and built several small animal imagers for use in biomedical research. "The DOE Office of Biological and Environmental Research put out a request a number of years ago for researchers to develop methods to image animals in a natural physiological state," Weisenberger explains. "The Detector Group responded to that. Our proposal was one of 17 out of about 70 white papers that DOE was interested in. We teamed up with researchers at Oak Ridge National Lab and Johns Hopkins University to propose the development of an imaging technology to image a mouse while it is still awake. Eventually, we were one of five projects that got funding."

According to Weisenberger, the imager Dr. Lee is using in his research is an offshoot of that project. "We're perfecting our system with the experience we're getting with our technology in different applications of animal research, like Dr. Lee's project," Weisenberger explains.

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