The study represents an important step in developing gene therapy for cystic fibrosis and other serious lung diseases.

Assem Ziady, Ph.D., assistant professor of pediatrics at the Case Western Reserve University School of Medicine, presented the results. He is conducting studies of a promising non-viral DNA nanoparticle technology that may prove to be effective in treating numerous human diseases. For this study, he collaborated with Zhenghong Lee, Ph.D., assistant professor of radiology and an expert in imaging.

In the study, Ziady and colleagues administered to CF mice DNA nanoparticles encoding a gene for an enzyme that produces light when exposed to a particular chemical. Later, the researchers could then use the emitted light to see in real time where the DNA nanoparticles had delivered the gene for expression in the lungs of the mice.

"Development of these real-time imaging modalities has allowed us to better assess the localization and site of activity of our gene transfer complex formulations," said Ziady. "Understanding gene transfer in animals is important in developing nucleic acid-based therapies to treat serious lung diseases such as cystic fibrosis."

The DNA nanoparticle technology is licensed to and being developed by Cleveland-based Copernicus Therapeutics, Inc. "Collaborations with scientists such as Dr. Ziady enable us to better develop nucleic acid therapeutics for different parts of the body and for multiple diseases," said Mark J. Cooper, M.D., senior vice president of Science and Medical Affairs of Copernicus. "Our lead program, which already has had a successful clinical trial, is development of a therapy for the lung complications of cystic fibrosis."

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The new HSPH analysis method, which uses just one dataset, bypasses the multiple comparison problem altogether by first estimating how much genetics can explain a specific trait within a population, and then tracing the roots of the trait back to candidate SNPs that would explain that "genetic effect size." To test their methodology, the research team ran simulation studies using data from the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study based at Channing Laboratory, Brigham and Women's Hospital, in Boston and data from a joint study conducted by the Mayo Clinic College of Medicine and Affymetrix. The results of the simulation studies suggested that the new approach outperformed the traditional approach by factors up to 100.

Besides dealing away with the multiple comparison problem, the HSPH technique offers another feature that is highly attractive to geneticists-the methodology appears to be able to find multiple SNPs involved in a single disease or trait.

"Many biomedical scientists today are interested in complex phenotypes, such as risk for unhealthy levels of body mass index, blood pressure, or cholesterol," said HSPH Assistant Professor of Biostatistics Christoph Lange, who is senior author on the paper. "Yet until now, no statistical tool existed that would allow researchers to look at several thousand disease genes and successfully identify those small number of genes that influence such complex traits."

The HSPH methodology is part of an analysis software program called PBAT, freely available at biostat.harvard/~clange/default.htm. The program was developed by Lange and HSPH Professor Nan Laird.

The CAMP Genetics Ancillary Study is supported by the National Heart, Lung, and Blood Institute. The joint study conducted by the Mayo Clinic College of Medicine and Affymetrix was supported by the Mayo Clinic Genomic Center and Comprehensive Cancer Center and by the National Institutes of Health (NIH). The NIH provided additional funding for the HSPH research.

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