Molecular Mechanisms in Amyloid Disorders. Novel Treatment Options in Hereditary Cystatin C Amyloid Angiopathy.
Author
Summary, in English
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.
Department/s
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:78
Full text
Document type
Dissertation
Publisher
Division of Clinical Chemistry and Pharmacology, Faculty of Medicine, Lund University
Topic
- Pharmacology and Toxicology
- Medicinal Chemistry
Keywords
- cystatin C
- amyloid
- amyloidosis
- oligomers
- domain swapping
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87449-50-5
Defence date
14 September 2013
Defence time
09:15
Defence place
Wallenberg Neurocenter, Segerfalksalen, BMC, Sölvegatan 17, Lund, Sweden
Opponent
- Elvar Theodorsson (Professor)