Vlachodimitropoulou Koumoutsea, E; (2017) Novel approaches to iron chelation therapy: novel combinations and novel compounds. Doctoral thesis , UCL (University College London).

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Abstract

Iron overload is an inevitable consequence of repeated blood transfusions required to sustain life in a wide array of haematological conditions such as thalassaemia, aplastic anaemia, and myelodysplastic syndromes (MDS). Without iron chelation therapy, death from cardiotoxic effects of iron overload usually ensues in the second decade. Iron chelation therapy with subcutaneous Desferrioxamine (DFO) infusions at least 5 nights per week has been shown unequivocally to prolong life expectancy in thalassaemia major. However, although this molecule is remarkably free of toxic side effects at treatment doses, patient compliance is often poor, and iron overload still leads to death today. One of the scopes of this Ph.D. was to develop a cellular model that would allow the testing of novel chelating agents used alone or in combination with established chelators. Our in vitro model of iron overload was able to elucidate several principles regarding the interactions of chelators within cells. It allowed for the first time a detailed interrogation of synergy as opposed to additivity of action of licensed chelators when used in combination, which has now been published. This model is also relevant to the development of new chelators and was used to demonstrate the iron binding properties of Eltrombopag (ELT), a drug used to manage ITP, at clinically achievable concentrations. ELT is a powerful intracellular iron chelator that decreases storage iron and enhances iron removal when in combination with commercially available iron chelators. In clinical use, donation of chelated iron by ELT to these chelators offers established routes for elimination of chelated iron. Furthermore, we extensively investigated the iron mobilising properties of the naturally occurring flavonoid quercetin and its principle metabolites. For the first time we showed that quercetin and its metabolites can act as a shuttle when combined with licensed chelators and provided a unique structure-function analysis of flavonoids with regards to iron and ferritn mobilisation and antioxidant capacity as a function of Fe(II) binding. A further goal of this thesis was to establish an iron-overloaded humanised thalassaemia mouse model that could be used to examine whether the same principles which determine iron release from cell cultures also influence the oral efficiency of iron chelators, in vivo. We utilised iron dextran to achieve cardiac iron loading confirmed by histology and MRI investigations. Iron overloaded mice were treated with a combination of the flavonoid quercetin and the iron chelator Deferasirox (DFX), and we established the value of this in combination in terms of cardiac iron mobilisation. Our novel humanised β thalassaemia ion-overloaded mouse model demonstrating cardiac iron loading is a first-in-kind development, and the novel application of MRI will provide a useful tool for studying iron chelators, the pathophysiology and disease progression, blood transfusion regimens and cellular/gene therapy in iron overload in the future. Our findings in vivo support the contention that our cellular model is a useful screening tool for new compounds, both for toxicity and efficacy.

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