Leslie, Anna Charlotte;
(2023)
Modulation of systemic sclerosis pathobiology by purified human factor XIII - in vitro and in vivo studies.
Doctoral thesis (M.D(Res)), UCL (University College London).
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Abstract
Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity, mortality and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, including thrombospondin-1 (TSP-1) signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation and in wound healing by promoting angiogenesis via inhibition of TSP-1. Animal research and previous small studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc. This thesis addresses the hypothesis that FXIII supplementation may affect the pathogenesis of SSc via effects on vascular and connective tissue biology. This is explored in two interlinked clinical trials: a single-dose open-label study assessing the safety and pharmacokinetics of human factor XIII treatment in SSc; followed by a phase II, double-blind, randomised, placebo-controlled study to investigate the safety and efficacy of factor XIII treatment in SSc. The main objective of the clinical trials was met by demonstrating that FXIII is safe and well tolerated in SSc. The trial did not meet its primary endpoints, but there was a trend towards improvement in Raynaud’s phenomenon in the FXIII group. Serum from patients and controls was analysed to quantify candidate biomarkers for SSc and the proposed mechanism of action of factor XIII. Previous work confirming that cartilage oligomeric protein, TSP-1 and tumour necrosis factor alpha are raised in SSc serum was reproduced. TSP-1 levels fell significantly in the serum of participants who received FXIII, supporting the hypothesis that FXIII modulates TSP-1. Further studies with different patient populations and FXIII doses could investigate the role of this suppression further in a clinical setting. My results support further exploration of the role of FXIII in SSc pathogenesis and suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D(Res) |
| Title: | Modulation of systemic sclerosis pathobiology by purified human factor XIII - in vitro and in vivo studies |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author's request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10163189 |
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