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Improving Diagnosis, Understanding, and Treatment of Farber Disease

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Improving Diagnosis, Understanding, and Treatment of Farber Disease Improving diagnosis, understanding, and treatment of Farber disease by Shaalee Dworski A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Shaalee Dworski 2017 Improving diagnosis, understanding, and treatment of Farber disease Shaalee Dworski Doctor of Philosophy Institute of Medical Science University of Toronto 2017 Abstract Farber disease (FD) is an ultra-rare Lysosomal Storage Disorder. It is caused by mutations in ASAH1, resulting in reduced activity of acid ceramidase and ceramide accumulation. The disease is poorly understood due to its rarity and the often short lifespan of patients. FD is systemic, with prominent hematological and sometimes neurological components. To better understand the disease, I characterized the hematopoietic and neurological effects of FD in the first mouse model, where the ASAH1 patient mutation P362R was knocked-in. Mice with FD have enlarged organs due to the accumulation of Mac-2+, foamy macrophages. This accumulation disrupts the organ architecture of hematopoietic-associated organs, including the BM and thymus, resulting in an almost complete loss of developing B and T cells in these organs, respectively, and an excess of hematopoietic stem and progenitor cells in the bone marrow. In the brain, mice with FD also have excess macrophages/microglia, astrocytosis, and hydrocephaly. To improve diagnosis of FD, I identified a plasma cytokine profile that distinguishes patients with FD from those with a disease that it is commonly misdiagnosed as, Juvenile Idiopathic Arthritis. The most elevated of these cytokines was monocyte chemotactic protein 1, and it alone or with the other elevated cytokines was associated with the presence of FD with 80% accuracy. These cytokines were normalized in FD patients who had received hematopoietic stem cell transplantation ii (HSCT). Finally, to reduce these signs of FD, I tested the efficacy of HSCT. HSCT from WT mice to FD mice more than doubled their lifespan from 7-13 weeks to a median of 27 weeks and a maximum of 40 weeks. Ceramide levels were normalized, and some peripheral signs of the disease were reduced. While beneficial, HSCT did not improve all symptoms. Through better diagnosis and understanding of FD, more effective treatments can be developed. iii Acknowledgments Thank you to my supervisor, Dr. Jeffrey Medin, for the opportunity that he has given me and for his ongoing support. Thank you to my committee members Dr. Armand Keating and Dr. Norman Iscove for their guidance and intellectual input. Thank you to the patients and their families who participated in these studies. I am thankful for the generous funding to study and travel to conferences provided during my PhD from the Canadian Institutes of Health Research (CIHR) Biological Therapeutics Program, the CIHR Institute Community Support Program, the Queen Elizabeth II/Dr. Dina Gordon Malkin Graduate Scholarship in Science and Technology, the Institute of Medical Science, the University of Toronto School of Graduate Studies, the University Health Network Office of Research Trainee, the WORLD Symposium, the American Society of Hematology, and the Garrod Society. For my father. iv Contributions Introduction and discussion The predicted mouse and human model of acid ceramidase was developed by Zi Jian Xiong. I annotated it with colour-coded mutations. Chapter 3 Figures and text adapted from Dworski et al., 2015 with permission from Haematologica. Jessa Trentadue and I photographed the mouse organs (Figure 10). Alexandra Berger, Joshua M. Moreau, and I planned and collected data for the flow cytometry (Figure 16-Figure 18; Figure 20). Caren Furlonger performed the IL-7 stimulation assays (Figure 19). The Centre for Modeling Human Disease (CMHD) performed the immunohistochemistry staining (Figure 11- Figure 14). Chapter 4 Figures and text adapted from Sikora & Dworski et al., 2017 with permission from the American Journal of Pathology. Jakub Sikora, Matthew C. Micsenyi, and Tomo Sawada performed the histological analysis of the brains of the mice (Figure 29A; Figure 30A,C; Figure 31-Figure 38). E. Ellen Jones performed the imaging mass spectrometry analysis of the brains of the mice (Figure 27; Figure 28). Pauline Le Faouder, Justine Bertrand-Michel, Aude Dupuy, Thierry Levade, Josefina Casas, and Gemma Fabrias identified the ceramide species present and I analyzed the data (Figure 25; Figure 26). Christopher K. Dunn performed the grip test and activity analysis under my supervision and I analyzed the data (Figure 24G,H). Ingrid Xuan v performed the open field test, rotarod test, and marble burying assay under my supervision (Figure 24A-F,I). Chapter 5 Joshua M. Moreau and Alexandra Berger assisted with planning the staining for flow cytometry and data collection (Figure 66). Jakub Sikora performed the histological analysis of the brains of the mice (Figure 67). Thierry Levade identified the ceramides in the organs and I analyzed the data (Figure 63). Maria (Mafe) Monroy and Sadiya Yousef performed the mouse tail vein injections for the hematopoietic stem cell transplantations. The Centre for Modeling Human Disease (CMHD) performed the immunohistochemistry staining (Figure 65). Chapter 6 Figures and text adapted from Dworski et al., 2017 with permission from Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. Ping Lu quantified the ceramide species in the mouse and human plasma samples (Figure 47-Figure 53). Xingxuan He and Edward H. Schuchman performed the acid ceramidase enzyme activity test on human plasma samples (Figure 46; Figure 56). vi Table of Contents Acknowledgments .......................................................................................................................... iv Contributions ................................................................................................................................... v Table of Contents .......................................................................................................................... vii List of Abbreviations .................................................................................................................. xvii List of Tables ............................................................................................................................... xxi List of Figures ............................................................................................................................. xxii Chapter 1 Literature Review ........................................................................................................... 1 1.1 Sphingolipids ...................................................................................................................... 1 1.1.1 Structure .................................................................................................................. 2 1.1.2 Source ..................................................................................................................... 2 1.1.3 Ceramide ................................................................................................................. 4 1.1.4 Ceramide metabolism ............................................................................................. 5 1.1.5 Difficulty in studying ceramides and sphingolipids ............................................... 6 1.2 Acid ceramidase .................................................................................................................. 8 1.2.1 Introduction ............................................................................................................. 8 1.2.2 Family ..................................................................................................................... 8 1.2.3 Gene ........................................................................................................................ 8 1.2.4 Protein ..................................................................................................................... 9 1.2.4.1 Enzyme activity ...................................................................................... 11 1.2.4.2 Reverse enzyme activity ......................................................................... 11 1.2.4.3 Extra-lysosomal function ........................................................................ 12 1.2.4.4 Apoptosis ................................................................................................ 12 1.2.5 Diseases relating to perturbed ACDase activity ................................................... 14 vii 1.3 Lysosomal Storage Disorders ........................................................................................... 15 1.3.1 Prevalence ............................................................................................................. 17 1.3.1.1 Difficulty in determining the prevalence of individual LSDs ................ 18 1.3.2 Diagnosis ............................................................................................................... 19 1.3.2.1 Methods .................................................................................................. 19 1.3.2.2 Different ages of diagnosis ..................................................................... 19 1.3.2.3 Carrier screening..................................................................................... 20 1.3.3 Treatments ............................................................................................................
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