Clinical Research on Inherited Metabolic Disorders
Raphael Schiffmann, M.D., M.H.Sc.
Research within this center is directed at understanding the primary mechanisms involved and developing novel therapies for specific genetic diseases with a focus on Fabry disease.
Dr. Schiffmann performs clinical research in Fabry disease; he is the principal investigator in treatment trials of novel therapies for Fabry disease. Treatment trials for novel therapies of neuronopathic Gaucher disease are planned.
He also studies a number of other rare but devastating genetic diseases including mucolipidosis type IV, and investigates disorders of unknown cause using a variety of tools including next-generation sequencing (http://www.neuroundiagnosed.com/Pages/default.aspx). Together with international collaborators, he finds the causal genetic defects in some of these disorders.
Research on Lysosomal Storage Disease
Jinsong Shen, M.D., Ph.D.
Dr. Shen performs basic and translational research of inherited metabolic disorders, specifically Fabry disease using animal models and in vitro cell culture systems.
His research direction is to identify underlying disease mechanisms in Fabry disease and to find new molecular targets for the treatments. One of his current research interests is to study the pathophysiology of small fiber neuropathy, one of the key features of Fabry disease.
He also studies mechanism of endocytosis of α-galactosidase A (the missing enzyme in Fabry disease) in disease-relevant cell types in order to develop approaches that may improve efficacy of enzyme replacement therapy.
Dr. Shen is also involved in preclinical studies on evaluating novel therapeutic products that were developed for Fabry and other glycosphingolipidoses by biotech companies.
Research on Folate, One-carbon Metabolism and Methylation
Teodoro Bottiglieri, Ph.D.
Translational research in Dr. Bottiglieri’s laboratory involves the use of transgenic animal mouse models to study the effects of dietary, genetic and/or drug induced alterations in folate metabolism on methylation dependent pathways.
His group has shown that folate deficiency causes hypo-methylation of proteins that leads to the accumulation of phosphorylated forms of Tau and amyloid proteins in the brain. These proteins play a primary role in the neuropathology of Alzheimer’s dementia and other neurodegenerative diseases.
We have recently demonstrated that a drug (L-dopa), used to treat Parkinson’s disease can affect methionine metabolism and lead to a hypo-methylation state and increase levels of phosphorylated Tau protein in the brain.
More recently, collaborative studies with Dr. Sontag (University of Newcastle Australia) have revealed that aging transgenic mice with a targeted deletion of the methylenetetrahydrofolate reductase (MTHFR) gene, which is a good model of the common human MTHFR (C677T) polymorphism, develop hypo-methylation of key regulatory enyzmes that are involved in the processing of phosphorylated forms of Tau protein in brain tissue.
Phosphorylated-Tau protein is neurotoxic and implicated as a causative factor in dementia and other neurodegenerative disorders. Our current studies are aimed at therapeutic strategies to target methylation in order to prevent the buildup of these toxic proteins.
We are also investigating how these mechanistic studies are relevant in understanding the downstream metabolic events in various sub-populations that have B-vitamin insufficiency, genetic mutations and/or drug induced interactions that can lead to a hypo-methylation state. Hypo-methylation may be an underlying cause in various disease states.