La Jolla, CA, November 9, 1998 - Idun Pharmaceuticals, Inc. today presented data on the cellular mechanism causing cell death during liver transplantation surgery at the American Association for the Study of Liver Diseases meeting in Chicago, IL. The research, titled "Selective Apoptosis of Sinusoidal Endothelial Cells Occurs During Ischemia/Reperfusion Injury of the Liver by a Caspase-Dependent Mechanism," was described in an oral presentation by Shiho Natori, M.D., of the Mayo Clinic in Rochester, MN and was co-authored by researchers at the Mayo Clinic and Idun.
In liver transplantation, the organ is temporarily deprived of oxygen while it is in transit between the donor and recipient. This deprivation is known as ischemia. Upon attachment to the recipient's circulatory system, blood and oxygen flow to the liver is re-established, a process known as reperfusion. While researchers have known that the ischemia/reperfusion, which occurs during transplantation, results in cell damage, the molecular pathway responsible for the damage had not been identified.
"Liver preservation injury is an important problem in transplantation surgery, but without a clear understanding of the mechanisms involved in the process we have not been able to prevent it or reduce its effects," said Karen Valentino, Ph.D., Director of Clinical Development at Idun and co-author on the paper. "These data show that liver ischemia/reperfusion injury induces a caspase-dependent apoptosis in endothelial cells. Now that we have identified which caspase is involved and which cell type is affected, we have the potential to develop therapies to intervene in the process and provide recipients with healthier livers."
Caspases are proteins that are known to play a role in programmed cell death (apoptosis). Researchers used a cell-based assay in combination with high-powered microscopy to detect apoptotic cells and to identify the type of affected cells in liver tissue sections. The assay, known as TUNEL, detects fragmented DNA, a hallmark of apoptosis. Transmission electron microscopy allows specific cell types to be identified visually. After determining that cell death resulted through an apoptotic pathway, scientists then added a compound known to inhibit caspase-3 in rat livers at various points of the liver preservation process. This compound, IDN-1965, is being developed by Idun. The data show that addition of IDN-1965 reduced apoptosis by 63 percent, as measured by the TUNEL assay.
"This research demonstrates that apoptosis plays a role in liver preservation injury and suggests that the process also may play an important role in ischemia/reperfusion damage in other organs and tissues as well," said Steven J. Mento, Ph.D., President and CEO of Idun. "We are very encouraged by the ability of IDN-1965 to reduce apoptosis-related cell death in liver transplantation injury and we will continue to evaluate the potential of this compound and other apoptosis-related compounds for treating a wide variety of diseases."
Idun Pharmaceuticals creates innovative human therapeutics with a primary focus on controlling apoptosis, or programmed cell death. In addition to its focus on small molecule inhibitors of apoptosis for applications in central nervous system disorders, cardiovascular disease, inflammation, and organ damage, Idun's drug discovery programs focus on small molecule activators of apoptosis for applications in cancer.
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