TY  - UNPB
Y1  - 2023/01/28/
AV  - public
EP  - 402
TI  - Modulation of systemic sclerosis pathobiology by purified human factor XIII - in vitro and in vivo studies
N1  - 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.
UR  - https://discovery.ucl.ac.uk/id/eprint/10163189/
PB  - UCL (University College London)
N2  - 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.
ID  - discovery10163189
A1  - Leslie, Anna Charlotte
M1  - Doctoral
ER  -