Dr. Daniel Ory on NP-C Disease

April 1, 2011. Daniel Ory, M.D. - Co-Director of the Diabetic Cardiovascular Disease Center and a Professor of Medicine, Cell Biology and Physiology at the Washington University School of Medicine in St. Louis, MO. Dr. Ory spoke in the CRND's Clinical Translational Seminar Series on the topic, "Niemann-Pick C Disease: Strategies and Challenges for Discovery of New Therapies." He is pictured above with students from the CRND's course in Developing Health Networks in Rare and Neglected Diseases.

Dr. Daniel Ory has the gift of presenting complex material with revealing simplicity. His seminar on NP-C Disease began with a review of the effects of mutations in npc1 and npc2 genes: a sequence of dysfunctional cellular states that eventually result in cytotoxic cholesterol and lipid accumulation and subsequent death. After outlining an initial column to trace the pathogenic process, Dr. Ory laid a parallel track along side it. The second track described the path of potential inventions that might mitigate or reverse disease processes at each stage. The effect of this display was to help students in class grasp the concept of biological substances or biomarkers that are characteristic of diseases states or therapeutic responses - in much the same way that signposts characterize the distance of any entrance/exit relative to the origin/terminus of a highway.

Dr. Ory discussed the need for biomarker identification and development in rare diseases such as NP-C, both for the purpose of screening potential patients and demonstrating the efficacy of potential drug treatments. According to Dr. Ory, the need for these quantifiable surrogate measures that correlate to clinical signs and symptoms of disease processes is especially urgent in the area of rare diseases. Because rare diseases have relatively small patient populations, it is difficult to find adequate (statistically significant) measures of the biological response to potential therapeutic agents or indicators of underlying incipient disease processes.

Finding biomarkers for rare diseases opens the possibility of detecting disease processes in early stages where potential treatments may be more efficacious.

Dr. Ory described the example of a potential biomarker for NP-C disease screening in infants where early diagnosis is seldom seen. The diagnosis of NP-C disease has been associated with an earlier history of transient neonatal jaundice. While the condition of jaundice often resolves in children who eventually develop NP-C, it would be helpful to have a screening method, which could be applied when infants present with transient neo-natal jaundice. The early identification of children who might develop NP-C would increase the ability of researchers to map the earliest stages of the pathway of the disease process and thus, identify points for earlier intervention.

Central to Dr. Ory's lively discussion with students in BIOS40450 was his current work with measuring oxysterols in the blood of NP-C patients as a foundation for using oxysterol levels as a biomarker for selective screening in NP-C. Dr. Ory described the high sensitivity and specificity of circulating oxysterols in NPC1 disease as indicators of disease progression and potentially the efficacy of therapies.

Daniel Ory's earned his undergraduate degree at Harvard College and his medical degree from Harvard Medical School in 1986. His internship, residency in medicine, clinical fellowship and research fellowship were at Brigham & Women's Hospital and Harvard Medical School. In the early nineties, Dr. Ory was a visiting scientist at the Whitehead Institute (MA) and Instructor in Medicine at the Harvard Medical School. In 1995, he moved to Washington University School of Medicine where he rose to Professor of Medicine (Cardiology) and Cell Biology & Physiology. In 2007, Dr. Ory became the Co-Director of the Diabetic Cardiovascular Disease Center at Washington University School of Medicine. Dr. Ory is the Faculty Director of Admissions at Washington University and a fellow of AAAS. Dr. Ory is on the Scientific Advisory Board for the National Niemann-Pick Disease Foundation.

Dr. Ory's work focuses on the mechanisms regulating cholesterol homeostatic pathways and the development of biomarkers for prevention and treatment of related human diseases. His approach is multidisciplinary, including biophysical, cell biology and steroid chemistry methods and his studies employing unbiased genetic screens have led to new discovery of small RNAs that regulate cellular cholesterol homeostasis. Candidate molecules identified by his approach are being examined in mouse models of atherosclerosis. Dr. Ory is also investigating the function and regulation of the Niemann-Pick C1 (NPC1) protein in cell-based and animal models. His studies use high throughput screens to identify small molecule “chaperones” that correct the protein-folding defect responsible for NPC1 disease and candidate compounds are being investigated in vivo in a mouse model of NPC1 disease. Using mass spectrometry-based lipidomic, Dr. Ory's team has identified candidate lipid metabolites that are being validated in clinical studies as biomarkers in human disorders associated with oxidative stress, including diabetes and Niemann-Pick C disease.


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