title: Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia.
abstract: β-thalassemia (βT) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of βT is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of βT in the γβ0/γβAhumanized mouse model of βT. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in βT. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical βT, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction- parameters essential for the preclinical development of new therapeutics.
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Jackson
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Vlachodimitropoulou
authors.affiliation: Institute for Women's Health, University College London, London, UK.
authors.forename: Panicos
authors.initials: P
authors.lastname: Shangaris
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ryan
authors.affiliation: Laboratory of Imaging Technology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda MD, USA.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Campbell-Washburn
authors.affiliation: Institute for Women's Health, University College London, London, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: David
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: John B
authors.initials: JB
authors.lastname: Porter
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stuckey
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging* / Q000503:physiopathology; D006801:Humans; D007501:Iron / Q000032:analysis / Q000378:metabolism; D019190:Iron Overload / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D017086:beta-Thalassemia / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology
chemical_list: D007501:Iron