Dr. Steven Walkley on NP-C Disease

March 4, 2011 - Dr.Steven Walkley (center, with beard) with students from the Course in Developing Health Networks in Rare and Neglected Diseases. From the left, Katrina Epperson, Aaron Patzwahl, Kevin Moser, Michael Clark, Dr. Walkley, Brianna McSorley, Lindsay Schwartz, Natalie Bott.

Steven U. Walkley, D.V.M., Ph.D. is the Director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center and the Head of the Sidney Weisner Laboratory of Genetic Neurological Disease. He is also a Professor for the Departments of Neuroscience, Pathology and Neurology at the Albert Einstein College of Medicine in New York.

With considerable intellectual zest, Dr. Walkley addressed students in BIOS40450 and the Clinical Translational Seminar Series audience on the history of Cyclodextrin research as a potential therapeutic in lysosomal disease. Dr. Walkley's seminar was entitled: "The Art of the Soluble: Cyclodextrin and Niemann-Pick Type C Disease."

Dr. Walkley's review of "the big picture" on lysosomal disease noted about 60 types of lysomsomal rare diseases, which cumulatively affect 1 out of every 7,500 people. Lysosomal diseases are characterized by the accumulation of material in the cellular organelles that break up cellular debris for disposal. The nature of the material accumulated defines the type of lysosomal disease. For example, Niemann-Pick Type C Disease (NP-C) is a progressive neurodegenerative lysosomal storage disease, which involves both the accumulation of cholesterol in neuronal cell bodies as well as gangliosides in the lysosomes. NP-C affects 1 out of every 120,000 individuals of Western European descent.

The discovery of Cyclodextrin as a potential therapeutic was both serendipitous and an outgrowth of careful scientific methodology. According to Dr. Walkley, investigators working with NP-C mice and cats were developing studies to build on earlier research, which suggested a role for Allopregnalone in reducing ganglioside and cholesterol storage in the cells. In the earlier research, Cyclodextrin was used as a "drug vehicle" with the expectation that its activity was neutral except for enhancing the delivery of Allopregnalone to cells. The new investigation tested Cyclodextrin and Allopregnalone independently to verify the foregoing assumption about Cyclodextrin as a mere vehicle. Instead of confirming the earlier study, the new research uncovered evidence for Cyclodextrin as an active agent in reversing the storage of gangliosides and cholesterol. Following the discovery of Cyclodextrin's operation, it was used in further experiments with Miglustat (a possible therapeutic for NP-C) to gauge its abilities to effect the survival of NP-C mice in comparison and in combination. So began a new and very promising investigative thread for the study of Cyclodextrin in NP-C research.

Dr. Walkley's challenging seminar led students and the CTSS audience through the complex process of hypothesis formulation and drug testing in animal models of NP-C and the myriad difficulties of mapping the pathogenesis of the disease. NP-C and many lysosomal diseases are complex because of the multiple unknown factors and processes, which combine in a cascade of effects over an extended period. Audience understanding was greatly enhanced by Dr. Walkley's excellent slides, illustrating the clear differences in treated and untreated cells across diverse tissue and drug administrations. UND students and faculty responded with excitement to the encouraging reports on the drugs under investigation in animal models and the provocative questions framed by Dr. Walkley throughout his engaging seminar.



Dr. Walkley joined the faculty of the Albert Einstein College of Medicine in 1982 after completing graduate and postgraduate studies at the University of Alabama in Birmingham, the University of Edinburgh, Auckland University in New Zealand and the Albert Einstein College of Medicine. Dr. Walkley's early training in veterinary and comparative medicine enabled his work in the identification and development of diseases in domesticated and laboratory animals. Dr. Walkley is on the Scientific Advisory Board for the National Niemann-Pick Disease Foundation. In 2007, he joined several other scientists in the formation of the NPC-SOAR project, the goal of which is the accelerated development of a therapy for Niemann-Pick type C disease.

Dr. Walkley investigates the pathobiology and treatment of genetic neurological diseases, cerebral cortical development and ganglioside function in neurons. Dr. Walkley's research centers on the analysis of pathogenic cascades and the development of therapeutic strategies for genetic disorders of the endosomal-lysosomal system (Tay-Sachs, Hurler, Sanfilippo, Niemann-Pick, Batten), which cause progressive neurological dysfunction and premature death. Dr. Walkley's studies include animal models of storage diseases. Studies explore the link between the primary protein defect, the abnormal accumulation of substrate (gangliosides, glycosaminoglycans, cholesterol), and subsequent changes in trafficking and signaling events within affected neurons. Therapeutic strategies addressed in Dr. Walkley's work include replacement of missing proteins through cell-mediated approaches (e.g., bone marrow transplantation) and substrate reduction therapy.




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