ࡱ> LNK'` s+bjbj 4>s#8888888L4444<p Lt!y y y  $`"h$!83y y 33!88.!3b88 3 88| `\'4. D!0t!z%z%z%8Dy , { ' y y y !!y y y t!3333LLL0LLL0LLL888888 APMRF Annual Scientific Conference Highlights In June, ninety researchers form around the world convened a meeting in Tucson, Arizona to discuss the advances in Niemann-Pick Type C (NP-C) disease research. These meetings were funded by a generous grant form the Bacon Family Foundation. In addition to the research presentations spanning two and half days, a full day was also devoted to the first ever clinical workshop co-sponsored by the National Institutes of Health. Summary of the presentations are located inside the newsletter. Matt Scott, Ph.D., Professor of Genetics, Cell and Developmental Biology at Stanford and a member of the APMRF SAB, chaired the Thursday morning session examining NPC1 protein structure and function. Rodney Infante, M.D., Ph.D., an APMRF Fellow in the laboratory of Nobel Prize laureates Michael Brown and Joe Goldstein at UT Southwestern presented a molecular model that explains how the NPC2 protein transfers cholesterol from within the lysosome to the NPC1 protein which resides in the limiting membrane. In collaboration with other scientists at UTSW the Brown and Goldstein group crystallized NPC1 N-terminal domain bound to cholesterol providing fundamental insights into the molecular basis of NPC1 structure and function. A manuscript describing these important contributions is in press. Guosheng Liang, Ph.D., who is also from UT Southwestern, created a genetically engineered mouse in which the NPC1 gene is conditionally targeted and can be ablated in specific cell types. This valuable reagent will be made available to the NPC research community. Suzanne Pfeffer, Ph.D., Professor of Biochemistry at Stanford, generated a series of tethered NPC1 domain mutants harboring mutations observed in human NPC1 patients. By expressing these mutant proteins she examined which human mutations block the function of NPC1 protein versus which proteins are simply mis-folded and inappropriately trafficked in the cell. These data may provide a basis for determining which human NPC1 mutations may be amenable to molecular chaperone therapies. Dr. Pfeffer used a novel native gel electrophoresis methodology to identify proteins that physically associate with an NPC1-containing protein complex. Kangaraj Subramanian, Ph.D., a post-doctoral fellow in the laboratory of Scripps Investigator and SAB member Bill Balch tested a series of NPC1 mutant proteins to distinguish which human mutations functionally disable the protein and which mutations lead to protein mis-folding. Similarly, Dan Ory, M.D., Ph.D., Associate Professor of Medicine at Washington University tested a series of NPC-1 mutant proteins harboring human mutations in the cysteine-rich domain. Like Dr. Pfeffers studies above, these experiments which were performed with recombinant full length NPC1 protein should provide insights into which human mutations may be amenable to molecular chaperone therapies. Judith Storch, Ph.D., and Peter Lobel, Ph.D. from Rutgers led a session examining the molecular basis of NPC2 protein function. Her studies complemented the research of Brown and Goldstein. Less than 5% of NPC cases are attributable to mutations in the NPC2 protein. John Dietschy, M.D., Professor of Medicine at UT Southwestern chaired an evening session on the cyclodextrin and NPC disease. Drs. Dietschy, Benny Liu, M.D. and Charina Ramirez, Ph.D. from UT Southwestern extended the findings described in their recent PNAS manuscript demonstrating that administration of cyclodextrin prolongs the life of NPC1 mutant mice. It also delays the onset of symptoms and, at least initially, improves the observed block in ganglioside and cholesterol storage within the cell. However, cyclodextrin did not cure NPC disease in mice; the longest surviving mice live approximately 6 months. Steven Walkley, D.V.M., Ph.D, and Cristin Davidson, Ph.D., from Albert Einstein College of Medicine, confirmed that administration of cyclodextrin to NPC1 mutant mice prolonged life and slowed onset of symptoms. They performed additional experiments examining different timing of cyclodextrin administration and different cyclodextrin formulations. Anton Rosenbaum, Ph.D. and Fred Maxfield, Ph.D., from Wiell-Cornell Medical Center, examined the mechanisms of action of cyclodextrin in NPC1 mutant cells. Charles Vite, Ph.D., D.V.M., from the University of Pennsylvania, reported that he has begun to test the efficacy of cyclodextrin and miglustat alone and in combination in NPC1 mutant cats. The studies have just begun and very little data is available, however, he has observed some toxicity which may be attributable to cyclodextrin in the NPC1 mutant cats. While this is potentially an important advance, many questions remain to be addressed including: i) whether cyclodexrin crosses the blood-brain barrier, ii) what form(s) of cyclodextrin possess potentially therapeutic actions, and iii) what toxicity is associated with short and long term administration of cyclodextrin? On Friday morning, Bill Balch, Ph.D. a Scripps Investigator and member of the SAB, chaired a session on NPC1 Neurobiology. Larry Goldstein, Ph.D., a HHMI Investigator and Professor of Neuroscience at UC San Diego, created a knockdown of the NPC1 gene in human ES cells and differentiated these cells into neurons. He reported that these neurons accumulate cholesterol and will be valuable reagent to examine the pathobiology of NPC disease in the brain. Manny Lopez, Ph.D., a postdoctoral fellow in the Scott laboratory at Stanford, demonstrated that expression of NPC1 protein in Purkinje neurons partially rescues Purkinje cell death observed in NPC1 mutant mice and slowed progression of disease. By contrast, expression of NPC1 protein in glial cells did not rescue Purkinje cell drop out in NPC1 mutant mice. Dr. Lopez also demonstrated that Toll-like receptor 7 is dramatically induced in NPC1 mutant Purkinje neurons. This is potentially relevant to the mechanism of NPC1 disease as Toll-like receptor 7 has been implicated in authophagy, a process whereby a cell engulfs itself. Joyce Repa, Ph.D., from UT Southwestern, is examining the interactions between neurons and glial cells in the pathogenesis of NPC disease. Her studies are focusing on the role of inflammatory cascades in the pathogenesis of NPC disease in the CNS. Matthew Elrick, M.D. from the University of Michigan generated genetically engineered mice with a conditional mutation in the NPC1 gene. He demonstrated that selectively ablating the NPC1 gene in Purkinje cells causes Purkinje cell death. Bill Pavan, Ph.D., a Senior Investigator in the NIH Human Genome Institute and SAB member, chaired the Friday afternoon session on NPC Genomics and other model systems. Shilipi Arora from TGen reported that she has performed an RNAi screen to identify genes that modulate cholesterol accumulation in NPC cells. Heiko Runz, M.D. from the University of Heidelberg in Germany, identified a novel protein TMEM97 that physically associates with NPC1 in the lysosome. Additional studies are underway characterizing the function of this protein. Denny Porter, M.D. from the NIH and Marc Patterson, M.D., from the Mayo Clinic, chaired the Saturday morning sessions focusing on clinical NPC research. Dr. Porter and Nicole Yanjanin, RN described the NPC Natural History Study which is being organized at the NIH. Dan Ory, M.D., Ph.D., reported that circulating oxidized cholesterol may serve as a biomarker of NPC disease. Studies are underway to determine whether oxidized cholesterol levels correlate with disease activity or progression. Kastruri Haldar, Ph.D. described the newly established Rare and Neglected Diseases program at Notre Dame. Paul Helquist, Ph.D., also from Notre Dame, described the combinatorial chemistry expertise of his laboratory which is being used to generate derivatives of therapeutic compounds that may be tested in NPC mutant mice and eventually NPC patients. The Clinical workshop spanned both Saturday afternoon and Sunday morning. The work shop was unique in its primary purpose to facilitate coordination of translational and clinical aspects of NPC on an international basis. The goals of the meeting were two fold; first, to promote interactions among basic scientists involved in preclinical testing of potential therapeutic agents in mouse models of the disease and clinical scientists studying NP-C, and second the meeting helped to promote interactions and collaborations between clinical scientists studying NP-C. Some of the topics discussed included the NIH observational trial, patient support and advocacy, and the need for a common NP-C patient registry. Further discussions were held on standardizing evaluations, including development of a severity scale, cognitive assessments and care of NP-C patients. 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