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Gerold Schmitt-Ulms, PhD

Grant Title: Bridging the pre-clinical gap for a small brain-penetrant molecule that reduces PrPC levels

Location: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto

Grant Year: 2024

A wide range of observations indicate that a reduction in the levels of the cellular prion protein (PrPC) is both safe and can extend survival of prion diseases. The promise that this treatment avenue offers has recently been validated in rodent studies, which evaluated antisense oligonucleotides or virus-delivered gene therapy vectors that ablate PrPC production. The clinical translation of these treatments to humans still faces formidable challenges in their safe delivery and the projected high costs of their broad dissemination.

This work will investigate a small molecule that has been optimized for reaching the brain after oral administration and reduces PrPC levels when assessed on a wide range of human cells. The treatment compound belongs to a clinically well understood compound class of cardiac glycosides that are inexpensive to produce. The main specific goal of this study is to establish if the oral administration of our lead compound can extend survival of prion diseases by lowering PrPC brain levels in an animal model. The study will also investigate if a PrPC lowering capacity of the compound in the brain can be monitored by drawing blood samples and measuring the PrPC levels in white blood cells at suitable intervals throughout the study.

About the Researcher:

Dr. Gerold Schmitt-Ulms studied biochemistry and genetics at the University of Hamburg, Germany. He obtained his PhD at the Max-Planck Unit for Structural Molecular Biology, Hamburg, investigating molecular interactions in Alzheimer’s disease under supervision of Dr. Eckhard Mandelkow. In 1999, he joined the laboratory of Dr. Stanley Prusiner, University of California San Francisco, to complement his training with the study of prion diseases. Since 2003, he has been a graduate faculty member within the Department of Laboratory Medicine & Pathobiology, University of Toronto, working at the Tanz Centre for Research in Neurodegenerative Diseases. His research focuses on Alzheimer’s disease, prion disorders and related dementias. More specifically, his group studies how disease perturbs the physiological function and molecular interactions of proteins known to cause inherited forms of these dementias. The overarching objective of this work is to derive mechanism-based early diagnostics and disease interventions.

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