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Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy

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Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy. Östner, Gustav 2013 Link to publication Citation for published version (APA): Östner, G. (2013). Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy. Division of Clinical Chemistry and Pharmacology, Faculty of Medicine, Lund University. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Molecular Mechanisms in Amyloid Disorders Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy GUSTAV RANHEIMER ÖSTNER Clinical Chemistry Department of Laboratory Medicine Lund University, Sweden DOCTORAL DISSERTATION by due permission of the Faculty of Medicine, Lund University, Sweden, to be defended at Wallenberg Neurocenter, Segerfalksalen, Sölvegatan 17, Lund, Saturday 14th of September 2013 at 9.15 a.m. Faculty opponent Professor Elvar Theodorsson Clinical Chemistry Department of Clinical and Experimental Medicine Linköping University, Sweden Organization Document name: LUND UNIVERSITY, Faculty of Medicine Doctoral Dissertation Dep. of Laboratory Medicine, Clinical Chemistry Date of issue: September 14th 2013 Author: Gustav Ranheimer Östner Sponsoring organization Title and subtitle: Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy. Abstract The pathophysiological process in Alzheimer’s disease and other amyloid disorders usually involves the transformation of a soluble monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. This has hampered the development of a deeper understanding of the molecular pathophysiology of the disorders and strategies for their treatment. In hereditary cystatin C amyloid angiopathy (HCCAA), a cystatin C variant is deposited in arterial walls and causes brain hemorrhage in young adults. Although carriers of the cystatin C variant may be easily identified by genetic testing, no treatments are available. In the present investigation, redox experiments involving a recombinant double-cysteine mutant of cystatin C were used to generate stable oligomers (dimers, trimers, tetramers, decamers and high-molecular-weight oligomers) and these were characterised concerning size, shape and function. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilised oligomers were used to induce antibody formation in rabbits. Oligomer-specific antibodies were obtained and these could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers. A miniaturised high-throughput system was developed and used to test 12 monoclonal antibodies and 1040 drugs in a clinical drug library for their capacity to reduce cystatin C dimer formation in vitro. Several candidates for treatment of HCCAA could be identified. In a different set of patients, scheduled for elective surgery, the plasma levels of cystatin C, creatinine and four inflammatory markers were studied in order to investigate the influence of inflammation on cystatin C, to evaluate its usefulness as a marker of glomerular filtration rate (GFR, ‘kidney function’). The cystatin C level did not change significantly during the observation period (seven days) and did not correlate with the level of any of the four inflammatory markers, and thus, the inflammatory status of a patient does not influence the role of cystatin C as a marker of GFR. Key words cystatin C, amyloid, amyloidosis, oligomers, domain swapping Classification system and/or index terms (if any) Supplementary bibliographical information Language: English ISSN and key title: 1652-8220 ISBN: 978-91-87449-50-5 Recipient’s notes Number of pages: 98 Price Security classification Signature Date Lund University, Faculty of Medicine Doctoral Dissertation Series 2013:78 Molecular Mechanisms in Amyloid Disorders Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy GUSTAV RANHEIMER ÖSTNER 2013 Cover: Cystatin C amyloid oligomers (green), formed by propagated domain swapping of ten monomeric subunits (i.e. decamers); antibody (blue), specific for oligomer epitopes; map, illustrating the scientific collaboration between Lund and Reykjavik. © Gustav Ranheimer Östner Clinical Chemistry Department of Laboratory Medicine Lund University Hospital, Sweden Lund University Faculty of Medicine Doctoral Dissertation Series 2013:78 ISBN 978-91-87449-50-5 ISSN 1652-8220 Printed in Sweden by Media-Tryck, Lund University Lund 2013 i To my beloved family ii iii The author on a field trip to Silfrá; a lagoon created by crystal clear water from a melting jökull. Tingvallavatn, Iceland, 2009. The author with his family in August 2013. The youngest member arrived in the middle of the preparation of this thesis. From left: Gustav, Sofia, Axel, Vilgot, Hulda, Baby Östner. iv Dissertation Committee Project Advisor: Anders Grubb, MD, Professor Clinical Chemistry, Department of Laboratory Medicine, Lund University, Sweden Assistant Advisor: Magnus Abrahamson, Associate Professor Head and Chair, Department of Laboratory Medicine, Lund University, Sweden Faculty Opponent: Elvar Theodorsson, MD, Professor Clinical Chemistry, Department of Clinical and Experimental Medicine, Linköping University, Sweden Examining Committee: Catharina Svanborg, MD, Professor Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Lund University, Sweden Katrin Mani, MD, Associate Professor Glycobiology, Department of Experimental Medical Science, Lund University, Sweden Daniel Otzen, Professor iNANO and Department of Molecular Biology and Genetics, Aarhus University, Denmark v Abstract The pathophysiological process in Alzheimer’s disease and other amyloid disorders usually involves the transformation of a soluble monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. This has hampered the development of a deeper understanding of the molecular pathophysiology of the disorders and strategies for their treatment. In hereditary cystatin C amyloid angiopathy (HCCAA), a cystatin C variant is deposited in arterial walls and causes brain hemorrhage in young adults. Although carriers of the cystatin C variant may be easily identified by genetic testing, no treatments are available. In the present investigation, redox experiments involving a recombinant double-cysteine mutant of cystatin C were used to generate stable oligomers (dimers, trimers, tetramers, decamers and high-molecular-weight oligomers) and these were characterised concerning size, shape and function. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilised oligomers were used to induce antibody formation in rabbits. Oligomer-specific antibodies were obtained and these could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers. A miniaturised high-throughput system was developed and used to test 12 monoclonal antibodies and 1040 drugs in a clinical drug library for their capacity to reduce cystatin C dimer formation in vitro. Several candidates for treatment of HCCAA could be identified. In a different set of patients, scheduled for elective surgery, the plasma levels of cystatin C, creatinine and four inflammatory markers were studied in order to investigate the influence of inflammation on cystatin C, to evaluate its usefulness as a marker of glomerular filtration rate (GFR, ‘kidney function’). The cystatin C level did not change significantly during the observation period (seven days) and did not correlate with the level of any of the four inflammatory markers, and thus, the inflammatory status of a patient does not influence the role of cystatin C as a marker of GFR. vi Sammanfattning på svenska (Summary in Swedish) Ett felaktigt protein som klumpar ihop sig i hjärnans blodkärl är orsaken till hjärnblödning och för tidig död hos unga islänningar. Sjukdomen är ärftlig och uppkommer på grund av en enda felaktig
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