DECEMBER 9, 2008--The Clayton Foundation for Research (Houston, TX), through its technology transfer entity the Research Development Foundation, has granted to Transgenomic (Omaha, NE) an exclusive license to patents covering a method for mitochondrial DNA (mtDNA) damage detection. The patents form the basis for the development of polymerase chain reaction (PCR) tests to diagnose cardiovascular disease, diabetes, degenerative diseases of aging, cancer, and other diseases. The technology works by measuring oxidative damage within mitochondria.
Mitochondria are organelles that produce the energy required for cells to function normally. As the "power plants" of the cell, they are highly sensitive to oxidative damage, which reduces energy production. Epidemiologic and biologic studies suggest that oxidative stress is a risk factor for cardiovascular death, but the absence of an accepted measure has limited the ability to determine whether reducing oxidative stress will reduce cardiovascular risk. The licensed technology uses a quantitative polymerase chain reaction (PCR) measurement of mtDNA damage, and is a sensitive and specific indicator of oxidative stress.
The method was invented by researchers at the University of Texas in the laboratory of Dr. Ben Van Houten. In collaboration with Dr. Marschall Runge, they demonstrated that mtDNA damage in blood cells occurs early in atherosclerosis, that aortic mtDNA damage increases with age, and that genetic background and diet both can influence the level of damage. Preliminary studies suggest that the level of mtDNA damage also correlates with a near-term risk of major adverse cardiovascular events. Hence, measurement of mtDNA damage may be useful for predicting coronary atherosclerotic heart disease.
Dr. Van Houten, now at the Hillman Cancer Center at the University of Pittsburgh, has published more than 30 papers using this technology to follow damage and repair in mitochondrial and nuclear genomes. His laboratory has also shown that mtDNA damage develops in the brains of older mice and in a chemical model of Parkinson's disease. "We have demonstrated that reactive oxygen species cause significantly more mitochondrial DNA damage than nuclear damage in cells from human to yeast, and I am enthusiastic about moving this exciting assay from the bench to the bedside," he said.
Dr. Runge, who is now chair of the Department of Medicine at the University of North Carolina at Chapel Hill School of Medicine, noted the value of a test for mtDNA damage developed for broad clinical application. He commented, "In collaboration with Transgenomic we will be able to pursue studies of large populations of individuals at risk of cardiovascular diseases, and determine the utility of this measure in patients who may benefit from therapies to reduce oxidative stress."
Craig Tuttle, CEO of Transgenomic, commented, "We are pleased to conclude a license with the Clayton Foundation to develop this technology, which it has supported for many years. The license complements Transgenomic's mtDNA mutation analysis capabilities, and demonstrates continued strategic commitment to the rapidly growing area of mitochondrial analysis for pharmacogenomic research and clinical applications."
Mitochondria are organelles that produce the energy required for cells to function normally. There are hundreds of mitochondria in each cell, and within each mitochondrion are approximately 5 to 10 circular mtDNA molecules. These are maternally inherited, distinct from nuclear DNA, and encode a small number of mitochondrial genes, including elements of the oxidative phosphorylation (OX-PHOS) machinery that manufactures ATP, the biochemical energy currency.
That same machinery can generate toxic by-products -- "oxygen free radicals" -- that can chemically damage surrounding molecules, including mtDNA. Damaged mtDNA causes the production of faulty or decreased OX-PHOS machinery, which then can increase the generation of oxygen free radicals, and so a vicious cycle is triggered that ultimately leads to a reduced energy supply ATP. The amount of damaged mtDNA thus is an inverse measure of cellular health: the less damage the healthier and the more damage the less healthy a cell is.
Transgenomic has specialized in the molecular diagnostics of mitochondrial disorders including whole mitochondrial genome sequence and pathogenic point mutation analysis, as well as assessment of nuclear genes associated with mitochondrial function, such as DNA polymerase gamma (POLG). In addition to the mtDNA damage assay, Transgenomic is developing other tests to assess mtDNA copy number and deletion.
Transgenomic's products include the WAVE DHPLC Systems, related consumables and assay kits, Cytogenetics automated systems, and Transgenomic Pharmacogenomics and Reference Laboratory Services. The WAVE is a Denaturing High Performance Liquid Chromatorgraphy (dHPLC) multi-platform instrument used in many nucleic acid analysis applications including Mutation Detection, Sizing, Quantitation, and Purification. The WAVE has UV and Fluorescence detector components and a Fragment Collector. The system uses Navigator Software to collect and display data peaks as chromatograms. The HPLC system works by using a hydrophobic cartridge that won't react with DNA or RNA.